J Echocardiogr DOI 10.1007/s12574-017-0338-4
REVIEW ARTICLE
Exercise stress echocardiography in hypertrophic cardiomyopathy Kengo Suzuki1 • Yoshihiro J. Akashi1
Received: 30 December 2016 / Revised: 19 April 2017 / Accepted: 28 April 2017 Ó Japanese Society of Echocardiography 2017
Abstract In this review, we make a comprehensive summary of exercise stress echocardiography in hypertrophic cardiomyopathy (HCM) and practical tips used in our hospital. The main objective of performing exercise stress echocardiography in patients with HCM is to evaluate left ventricular outflow tract obstruction, mitral regurgitation, left ventricular asynergy, and diastolic function during exercise. There are limitations to the explanations that can be provided for exertional symptoms when resting echocardiography is performed in patients with HCM. In contrast, exercise stress echocardiography causes the manifestation of findings that are latent at rest, which possibly provides the elucidation of symptom etiology. In this article, we focus on the usefulness of exercise stress echocardiography in HCM.
Meanwhile, left ventricular outflow tract (LVOT) obstruction (LVOTO), systolic anterior motion (SAM) of the mitral valve, mitral regurgitation (MR), and ventricular asynergy are possibly induced during stress testing in patients with HCM even though no changes are present during echocardiography at rest. Exercise stress echocardiography provides an objective evaluation of ECG findings, blood pressure, heart rate, and exercise capacity (maximum stress dose and exercise duration) and facilitates elucidation of symptom etiology. The main objective of performing stress echocardiography in patients with HCM is to evaluate LVOTO, SAM, MR, and ventricular asynergy. In this review, we focus on the usefulness of exercise stress echocardiography in HCM. Stress echocardiography in HCM
Keywords Exercise stress echocardiography Hypertrophic cardiomyopathy Left ventricular outflow tract obstruction Systolic anterior motion of the mitral valve
Introduction It is common to perform echocardiography in addition to Holter electrocardiography (ECG) and exercise ECG in patients with hypertrophic cardiomyopathy (HCM) complaining of exertional dyspnea, chest pain, and syncope. Generally, echocardiography is only performed at rest. & Kengo Suzuki [email protected] 1
Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
The methods for performing stress echocardiography in HCM include the Valsalva stress test, standing stress test, exercise stress test, and pharmacological stress test. A treadmill (standing), an ergometer (sitting), or a supine ergometer (semi-supine or supine) is used for exercise stress testing. Dobutamine, isoproterenol, and amyl nitrate are administered during pharmacological stress testing; however, the 2014 European Society of Cardiology (ESC) guidelines for HCM do not recommend dobutamine stress testing as a form of stress echocardiography [1]. Dobutamine stress testing is not physiological in terms of the volume status and cardiac condition. That is, dobutamine increases cardiac contractility without an increase of preload, resulting in decreased LV end-systolic dimension and increased intraventricular pressure gradient even in healthy individuals. The findings during dobutamine stress testing in HCM patients are not considered to be related to symptoms during exertion or exercise tolerance [2]. By
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contrast, physiological exercise stress testing is recommended for HCM patients because it provides customized exercise and information related to exertional symptoms and exercise tolerance appearing during daily activities. The echocardiographic evaluation takes place after the exercise stress test when using a treadmill or during the exercise stress test when using a supine ergometer. Exercise stress testing using supine ergometers is often employed [3] because it has few problems with data recording compared to exercise stress testing using a treadmill; whereas the lower maximum stress dose and the reproducibility of clinical symptoms are the disadvantages [4]. Various studies have reported exercise stress echocardiography in HCM patients using treadmills, sitting ergometers, and supine ergometers; however, it remains controversial as to which stress test method should be selected. In addition, several factors, such as dehydration, diuretics, use of vasodilator agents, and diet, are known to affect LVOTO. Since LVOTO is also influenced by exercise stress echocardiography in HCM patients, efforts are being made to standardize a testing protocol [5]. The safety of exercise stress echocardiography in HCM has been established. The incidence of severe complications, such as death, cardiac arrest, and atrial or ventricular arrhythmias that require defibrillation, has been reported as 1 in 263 (0.04%) [6]. However, we should be aware that this test has the potential risk of these complications, particularly in patients who have a history of presyncope or syncope, extremely high intracardiac gradient at rest ([90 mmHg), or those with prior studies demonstrating a decrease in blood pressure with stress [4, 6]. Accordingly, exercise stress testing must be performed after sufficient preparation. It is advisable to ensure adequate space available and prepare an emergency cart stocked with emergency drugs and airway devices, a stress test monitoring system, including automated sphygmomanometer and 12-lead ECG monitor, a defibrillator, and oxygen. The ESC HCM guidelines [1] recommend the early evaluation of all HCM patients using sitting, semi-supine Valsalva or standing stress testing in addition to that of LVOTO. The guidelines also recommend exercise stress echocardiography in symptomatic HCM patients finding peak LVOT gradient \50 mmHg (Table 1). Prior to exercise stress echocardiography at our hospital, an informed consent form is used as a guide for the explanation of its method and the identification of the most recent symptoms and current medications. These symptoms sometimes worsen until a patient undergoes exercise stress echocardiography; thus, it is important to reconfirm the patient’s condition immediately before the test. Thereafter, we perform echocardiography at rest and examine the following: the morphology and degree of hypertrophy; SAM; the morphology of the tissues forming
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the mitral complex; LVOTO; and the degree of MR. LVOTO can also be evaluated using pulsed Doppler and continuous-wave Doppler in addition to Valsalva stress testing. Next, a supine ergometer is used for exercise stress testing according to the Bruce protocol, increasing exercise load by 25 W every 3 min. At our hospital, we employ the ramp exercise protocol for the elderly patients with remarkably decreased lower-limb strength. After a 3-min warm-up at 10 W, exercise load is gradually increased by 10 W every 3 min. Fundamentally, stress testing is performed until it is either limited by symptoms or 85% of the maximum heart rate is achieved. Exercise testing is interrupted at the following conditions: (1) blood pressure increases to C250/120 mmHg; (2) blood pressure decreases C10 mmHg compared to pre-test blood pressure; (3) sustained tachyarrhythmia or extensive hypokinesia occurs; and (4) subjective symptoms, including chest pain, occurs. While examining LVOTO, MR, SAM, and changes in wall motion with a supine ergometer, recorded echocardiograms during exercise provide necessary information at each stage of the exercise protocol. LVOTO LVOTO evaluation is the most important aspect of exercise stress echocardiography in HCM patients. LVOTO is defined as peak LVOT gradient C30 mmHg (flow velocity: 2.7 m/s) [2]. Latent LVOTO is defined as LVOTO that is not observed during echocardiography at rest but is induced by exercise stress testing (Fig. 1). LVOTO is known to be a risk factor for sudden death in HCM patients, although no consensus has been reached to date on whether latent LVOTO is a risk factor for sudden death or severe cardiovascular events [1]. The factors inducing LVOTO during exercise stress testing are summarized in Table 2 [3]. One study has reported that, of all HCM patients, 37% of patients reveal LVOTO at rest (hypertrophic obstructive cardiomyopathy), 33% of patients have latent LVOTO induced by exercise stress testing, which is not observed at rest, and 30% of patients have true nonobstructive HCM in which no LVOTO is observed either at rest or during exercise stress testing [7]. Shah et al. reported that approximately two out of three symptomatic HCM patients with chest pain, those with shortness of breath, those with presyncope, who showed no LVOTO at rest, had latent LVOTO [8]. This emphasizes the importance of evaluating LVOTO during exercise stress echocardiography when any symptoms are present during exertion, even if LVOTO is not observed during echocardiography at rest. Echocardiographic findings reported to cause LVOTO include hypertrophy of the basal interventricular septum, narrowing of LVOT (B2 cm), and a steep
J Echocardiogr Table 1 Recommendation for exercise echocardiography in hypertrophic cardiomyopathy Source: Elliott et al. [1] Recommendations
Class
Level
In all patients with HCM at initial evaluation, transthoracic 2D and Doppler echocardiography are recommended, at rest and during Valsalva maneuver in the sitting and semi-supine positions—and then on standing if no gradient is provoked
I
B
In symptomatic patients with a resting or provoked peak instantaneous LV outflow tract gradient \50 mmHg, 2D and Doppler echocardiography during exercise in the standing, sitting or semi-supine position is recommended to detect provocable LVOTO and exercise-induced mitral regurgitation
I
B
In asymptomatic patients with a resting or provoked peak instantaneous LV outflow tract gradient \50 mm Hg, 2D and Doppler echocardiography during exercise—in the standing, sitting, or semi-supine positions—may be considered when the presence of an LVOT gradient is relevant to lifestyle advice and decisions on medical treatment
IIb
C
Fig. 1 Latent left ventricular outflow tract obstruction (LVOTO). LVOTO is defined as not being observed at resting echocardiography but induced by exercise stress testing. 2D and Doppler echocardiography during a Valsalva maneuver, in the sitting and semi-supine Table 2 Factors contributing to dynamic left ventricular outflow tract obstruction Source: Otto [3]
positions and then on standing if no gradient is provoked, is recommended in all patients. Exercise stress echocardiography is performed in symptomatic patients when bedside manoeuvers fail to induce LVOTO C50 mmHg
Narrowing of left ventricular outflow tract Septal hypertrophy Anterior displacement of the mitral apparatus Anterior displacement of the papillary muscles Hydrodynamic forces (venturi and drag forces) causing systolic anterior motion Rapid early LV ejection Elongated mitral leaflets
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angle between the long axis of the left ventricle and the ejection flow (C35°) [9]. In contrast to exercise-induced LVOTO occurring in HCM patients, some studies have reported HCM in which LVOTO is alleviated by exercise stress testing. One report demonstrated that nine out of 38 HCM patients (24%) exhibited a paradoxical response; that is, LVOTO was alleviated by exercise stress testing and these patients had a low incidence of cardiovascular events [10]. It is difficult to observe this phenomenon after exercise stress testing using a treadmill because LVOTO often reappears after the test. To understand this phenomenon, LVOTO needs to be evaluated during exercise using an ergometer (Fig. 2). The procedures to alleviate LVOTO, such as a septal myectomy (Morrow procedure) and percutaneous transluminal septal myocardial ablation, are indicated for class I symptomatic patients with LVOTO at rest who are resistant to drug therapy. However, these procedures are also indicated for class I symptomatic cases with maximum peak LVOT gradient C50 mmHg during exercise stress testing
even if LVOTO is not observed at rest [1]. Exercise stress echocardiography is also useful for determining the postoperative effectiveness of these therapeutic procedures [3].
Fig. 2 A case of asymptomatic HCM with reduced LVOTO during exercise stress testing. The patient presented with a paradoxical response, i.e., a peak LVOT gradient of 100 mmHg at rest that decreased to 62 mmHg during peak exercise. The reduction in LVOTO was not observed in this patient during the evaluation
performed after exercise stress testing on a treadmill because it rapidly reappeared after the stress test was completed. Although highgrade LVOTO was observed at rest, to date, the patient’s clinical course has been improved without any symptoms of cardiac failure or arrhythmic events
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MR MR in HCM patients is caused by SAM of the mitral valve or the abnormalities of the mitral complex (valve cusp, chorda tendineae, and papillary muscles). MR is reported to trigger dynamic changes (Fig. 3) influenced by the degree of LVOTO during exercise stress testing [11]. Exercise plays a primary role in dynamic LVOTO obstruction due to a hyperdynamic left ventricle with a small cavity and SAM of the mitral valve leaflet. SAM is possibly associated with MR. It may also be complicated by morphological abnormalities of the tissues forming the mitral complex in patients with HCM [12] and have no associations with the degree of LVOTO or the severity of MR in some cases [13]. MR must be assessed while
J Echocardiogr Fig. 3 Exercise-induced systolic anterior motion (SAM)—mitral regurgitation (MR) in HCM. Although SAM or LVOTO was not observed at rest and only mild MR was identified, SAM and LVOTO were induced during exercise stress testing and the MR increased dynamically. Right ventricular systolic pressure (RVSP) increased from 33 mmHg to 63 mmHg. These findings indicated exerciseinduced pulmonary hypertension
evaluating LVOTO during exercise stress echocardiography in HCM patients [1]. Since there are some difficulties to distinguish MR signals from LVOT blood flow signals, special caution is required during measurement. These signals can be distinguished according to the following facts: the MR velocity curve shows a sharp increase in velocity at early systole with the slope reflecting the rate of rise in LV pressure, whereas the LVOT velocity gradually increases during early systole with an abrupt increase in velocity in mid- to late-systole as obstruction worsens in conjunction with SAM. In addition, MR signals have a long duration, extend beyond the second heart sounds, and continue until the mitral valve opens. The flow velocity of MR is always higher than that of the LVOT [3]. LVOTO will be overestimated when a MR signal is misrecognized as a LVOT blood flow signal; therefore, extreme caution is required during evaluation.
Left ventricular wall motion abnormality Peteiro et al. performed exercise stress testing in 239 HCM patients and found ventricular asynergy during exercise stress testing in 19 patients (7.9%). They reported that left ventricular asynergy was an independent predictive factor for cardiac-related death and serious events, such as cardiac transplantation [14]. Reant et al. investigated prognoses in 115 HCM patients and demonstrated that, even though left ventricular ejection fraction was maintained during resting echocardiography, there were some cases with decreased global longitudinal strain during exercise and it predicted serious events [15]. Their study results suggested that any findings demonstrating latent ischemia might predict prognosis. Irrespective of the detection of LV wall motion abnormalities, clinical symptoms and examination findings suggesting myocardial ischemia, such as chest pain, chest discomfort, abnormal Q waves, and ST-T changes, are
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frequently observed in patients with HCM [16]. These are due to (1) hypertrophy of the coronary arteriolar media and intima layers and decreased vasodilatory reserve, (2) compression stenosis of the intramyocardial coronary vessels, particularly the septal branches triggered by the contracting myocardium, (3) decreased diastolic coronary artery flow caused by impaired left ventricular relaxation, (4) increased intraventricular pressure triggered by LVOTO, and (5) decreased capillary density caused by hypertrophy and restricted subendocardial myocardial perfusion. These findings suggest that the presence of ischemia in HCM patients should be associated with prognosis and an evaluation of wall motion be required during exercise stress echocardiography.
briefly asymptomatic clinical course, although, NYHA Class II dyspnea on effort was detected. Exercise stress echocardiography was then requested. No LVOTO, MR or wallmotion abnormalities were observed at rest or during exercise echocardiography. The indices of left ventricular diastolic function increased from 0.8 to 1.7 (E/A) and from 8.5 to 13.0 (E/e0 ). The estimated pulmonary artery systolic pressure increased from 18 to 55 mmHg. These findings indicated exercise-induced pulmonary hypertension. Patients with apical HCM are generally considered as having favorable prognoses, although some patients have reduced diastolic function reserve. These patients should be subject to conscientious follow-up observation. Conclusions
Diastolic function Our previous study has reported the importance of diastolic function reserve in HCM patients [17]. We performed exercise stress echocardiography and cardiopulmonary exercise testing in 33 HCM patients. Although there were no associations between the echocardiographic indicators at rest and exercise capacity, we could find a strong correlation between the early diastolic longitudinal strain rate (LSR) during exercise and exercise capacity. Particularly, the changes in the LSR (diastolic function reserve) were an independent prognostic factor for exercise capacity; thus, the LSR was useful for the prediction of exercise capacity during exercise stress echocardiography in HCM patients (Fig. 4). Figure 5 presents a case of apical HCM that we encountered at our hospital. The patient was a 66-year-old man. A detailed ECG examination resulted in apical HCM. He had a
Patients with HCM present a variety of clinical symptoms; some of them may cause sudden death. It is quite difficult to define that patients with HCM have good prognoses. The evaluation of the subjective symptoms and risk factors for sudden death in detail and the presence of subjective symptoms are required for decision-making in the treatment of these patients. Meanwhile, the subjective symptoms by their very nature are matters to be concerned. When these symptoms prevent decision-making, we recommend that exercise stress echocardiography be performed. There are a number of patients who are incidentally diagnosed as being asymptomatic in the outpatient department but they have remarkable dyspnea in their daily activities. ECG, blood pressure, heart rate, and exercise capacity should objectively be evaluated during exercise; that is, these measurements contribute to the understating of one’s status
Fig. 4 Relationship between left ventricular strain during exercise and exercise capacity (cited from [17]). A significant positive correlation between the LSRe during exercise and peak VO2 was observed
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J Echocardiogr Fig. 5 A patient with apical HCM complaining of exertional dyspnea. No LVOTO, MR, or wall-motion abnormalities were observed at rest, nor were these findings observed during exercise stress echocardiography. However, the echocardiographic indicators of left ventricular dilation increased from 0.8 to 1.7 (E/ A) and from 8.5 to 13.0 (E/e0 ); Right ventricular systolic pressure (RVSP) increased from 18 to 55 mmHg. These findings indicated exercise-induced pulmonary hypertension
on exertion. Most of the published reports concerning exercise stress echocardiography in HCM patients are the single-center studies and, to date, there is no standardized protocol. In the 2014 ESC HCM guidelines, exercise stress echocardiography is recommended for
class I patients. Since the importance of exercise stress echocardiography in HCM has been widely recognized, a multi-center study of exercise stress echocardiography is thus called for the standardization of the protocol in Japan.
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References 1. Elliott PM, Anastasakis A, Authors/Task Force members, et al. ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC). Eur Heart J. 2014;2014(35):2733–79. 2. Otto CM. Textbook of clinical echocardiography. 5th ed. Philadelphia: Elsevier; 2013. p. 234. 3. Otto CM. Practice of clinical echocardiography. 4th ed. Philadelphia: Elsevier; 2012. p. 281. 4. Owens DS, Otto CM. Exercise testing for structural heart disease. In: Gillam L, Otto CM, editors. Advanced approaches in echocardiography. Philadelphia: Saunders; 2012. 5. Petkow Dimitrow P, Cotrim C, Cheng TO. Need for a standardized protocol for stress echocardiography in provoking subaortic and valvular gradient in various cardiac conditions. Cardiovasc Ultrasound. 2014;12:26. 6. Drinko JK, Nash PJ, Lever HM, et al. Safety of stress testing in patients with hypertrophic cardiomyopathy. Am J Cardiol. 2004;93:1443–4. 7. Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114:2232–9. 8. Shah JS, Esteban MT, Thaman R, et al. Prevalence of exerciseinduced left ventricular outflow tract obstruction in symptomatic patients with non-obstructive hypertrophic cardiomyopathy. Heart. 2008;94:1288–94. 9. Nakatani S, Marwick TH, Lever HM, et al. Resting echocardiographic features of latent left ventricular outflow obstruction in hypertrophic cardiomyopathy. Am J Cardiol. 1996;78:662–7.
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10. Lafitte S, Reant P, Touche C, et al. Paradoxical response to exercise in asymptomatic hypertrophic cardiomyopathy: a new description of outflow tract obstruction dynamics. J Am Coll Cardiol. 2013;62:842–50. 11. Peteiro J, Montserrat L, Castro-Beiras A. Labil subaortic obstruction during exercise stress echocardiography. Am J Cardiol. 1999;84:1119–23. 12. Ryan K, Murphy RT, DiPaola LM, et al. Mitral valve abnormalities in hypertrophic cardiomyopathy: echocardiographic features and surgical outcomes. Ann Thorac Surg. 2008;85:1527–35. 13. Fighali S, Krajcer Z, Edelman S, et al. Progression of hypertrophic cardiomyopathy into a hypokinetic left ventricle: higher incidence in patients with midventricular obstruction. J Am Coll Cardiol. 1987;9:288–94. 14. Peteiro J, Bouzas-Mosquera A, Fernandez X, et al. Prognostic value of exercise echocardiography in patients with hypertrophic cardiomyopathy. J Am Soc Echocardiogr. 2012;25:182–9. 15. Reant P, Reynaud A, Pillois X, et al. Comparison of resting and exercise echocardiographic parameters as indicators of outcomes in hypertrophic cardiomyopathy. J Am Soc Echocardiogr. 2015;28:194–203. 16. Sherrrid MV, Mahenthiran J, Casteneda V, et al. Comparison of diastolic septal perforator flow velocities in hypertrophic cardiomyopathy versus hypertensive left ventricular hypertrophy. Am J Cardiol. 2006;97(1):106–12. 17. Mizukoshi K, Suzuki K, Yoneyama K, et al. Early diastolic function during exertion influences exercise intolerance in patients with hypertrophic cardiomyopathy. J Echocardiogr. 2013;11:9–17.
REVIEW ARTICLE
Exercise stress echocardiography in hypertrophic cardiomyopathy Kengo Suzuki1 • Yoshihiro J. Akashi1
Received: 30 December 2016 / Revised: 19 April 2017 / Accepted: 28 April 2017 Ó Japanese Society of Echocardiography 2017
Abstract In this review, we make a comprehensive summary of exercise stress echocardiography in hypertrophic cardiomyopathy (HCM) and practical tips used in our hospital. The main objective of performing exercise stress echocardiography in patients with HCM is to evaluate left ventricular outflow tract obstruction, mitral regurgitation, left ventricular asynergy, and diastolic function during exercise. There are limitations to the explanations that can be provided for exertional symptoms when resting echocardiography is performed in patients with HCM. In contrast, exercise stress echocardiography causes the manifestation of findings that are latent at rest, which possibly provides the elucidation of symptom etiology. In this article, we focus on the usefulness of exercise stress echocardiography in HCM.
Meanwhile, left ventricular outflow tract (LVOT) obstruction (LVOTO), systolic anterior motion (SAM) of the mitral valve, mitral regurgitation (MR), and ventricular asynergy are possibly induced during stress testing in patients with HCM even though no changes are present during echocardiography at rest. Exercise stress echocardiography provides an objective evaluation of ECG findings, blood pressure, heart rate, and exercise capacity (maximum stress dose and exercise duration) and facilitates elucidation of symptom etiology. The main objective of performing stress echocardiography in patients with HCM is to evaluate LVOTO, SAM, MR, and ventricular asynergy. In this review, we focus on the usefulness of exercise stress echocardiography in HCM. Stress echocardiography in HCM
Keywords Exercise stress echocardiography Hypertrophic cardiomyopathy Left ventricular outflow tract obstruction Systolic anterior motion of the mitral valve
Introduction It is common to perform echocardiography in addition to Holter electrocardiography (ECG) and exercise ECG in patients with hypertrophic cardiomyopathy (HCM) complaining of exertional dyspnea, chest pain, and syncope. Generally, echocardiography is only performed at rest. & Kengo Suzuki [email protected] 1
Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
The methods for performing stress echocardiography in HCM include the Valsalva stress test, standing stress test, exercise stress test, and pharmacological stress test. A treadmill (standing), an ergometer (sitting), or a supine ergometer (semi-supine or supine) is used for exercise stress testing. Dobutamine, isoproterenol, and amyl nitrate are administered during pharmacological stress testing; however, the 2014 European Society of Cardiology (ESC) guidelines for HCM do not recommend dobutamine stress testing as a form of stress echocardiography [1]. Dobutamine stress testing is not physiological in terms of the volume status and cardiac condition. That is, dobutamine increases cardiac contractility without an increase of preload, resulting in decreased LV end-systolic dimension and increased intraventricular pressure gradient even in healthy individuals. The findings during dobutamine stress testing in HCM patients are not considered to be related to symptoms during exertion or exercise tolerance [2]. By
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contrast, physiological exercise stress testing is recommended for HCM patients because it provides customized exercise and information related to exertional symptoms and exercise tolerance appearing during daily activities. The echocardiographic evaluation takes place after the exercise stress test when using a treadmill or during the exercise stress test when using a supine ergometer. Exercise stress testing using supine ergometers is often employed [3] because it has few problems with data recording compared to exercise stress testing using a treadmill; whereas the lower maximum stress dose and the reproducibility of clinical symptoms are the disadvantages [4]. Various studies have reported exercise stress echocardiography in HCM patients using treadmills, sitting ergometers, and supine ergometers; however, it remains controversial as to which stress test method should be selected. In addition, several factors, such as dehydration, diuretics, use of vasodilator agents, and diet, are known to affect LVOTO. Since LVOTO is also influenced by exercise stress echocardiography in HCM patients, efforts are being made to standardize a testing protocol [5]. The safety of exercise stress echocardiography in HCM has been established. The incidence of severe complications, such as death, cardiac arrest, and atrial or ventricular arrhythmias that require defibrillation, has been reported as 1 in 263 (0.04%) [6]. However, we should be aware that this test has the potential risk of these complications, particularly in patients who have a history of presyncope or syncope, extremely high intracardiac gradient at rest ([90 mmHg), or those with prior studies demonstrating a decrease in blood pressure with stress [4, 6]. Accordingly, exercise stress testing must be performed after sufficient preparation. It is advisable to ensure adequate space available and prepare an emergency cart stocked with emergency drugs and airway devices, a stress test monitoring system, including automated sphygmomanometer and 12-lead ECG monitor, a defibrillator, and oxygen. The ESC HCM guidelines [1] recommend the early evaluation of all HCM patients using sitting, semi-supine Valsalva or standing stress testing in addition to that of LVOTO. The guidelines also recommend exercise stress echocardiography in symptomatic HCM patients finding peak LVOT gradient \50 mmHg (Table 1). Prior to exercise stress echocardiography at our hospital, an informed consent form is used as a guide for the explanation of its method and the identification of the most recent symptoms and current medications. These symptoms sometimes worsen until a patient undergoes exercise stress echocardiography; thus, it is important to reconfirm the patient’s condition immediately before the test. Thereafter, we perform echocardiography at rest and examine the following: the morphology and degree of hypertrophy; SAM; the morphology of the tissues forming
123
the mitral complex; LVOTO; and the degree of MR. LVOTO can also be evaluated using pulsed Doppler and continuous-wave Doppler in addition to Valsalva stress testing. Next, a supine ergometer is used for exercise stress testing according to the Bruce protocol, increasing exercise load by 25 W every 3 min. At our hospital, we employ the ramp exercise protocol for the elderly patients with remarkably decreased lower-limb strength. After a 3-min warm-up at 10 W, exercise load is gradually increased by 10 W every 3 min. Fundamentally, stress testing is performed until it is either limited by symptoms or 85% of the maximum heart rate is achieved. Exercise testing is interrupted at the following conditions: (1) blood pressure increases to C250/120 mmHg; (2) blood pressure decreases C10 mmHg compared to pre-test blood pressure; (3) sustained tachyarrhythmia or extensive hypokinesia occurs; and (4) subjective symptoms, including chest pain, occurs. While examining LVOTO, MR, SAM, and changes in wall motion with a supine ergometer, recorded echocardiograms during exercise provide necessary information at each stage of the exercise protocol. LVOTO LVOTO evaluation is the most important aspect of exercise stress echocardiography in HCM patients. LVOTO is defined as peak LVOT gradient C30 mmHg (flow velocity: 2.7 m/s) [2]. Latent LVOTO is defined as LVOTO that is not observed during echocardiography at rest but is induced by exercise stress testing (Fig. 1). LVOTO is known to be a risk factor for sudden death in HCM patients, although no consensus has been reached to date on whether latent LVOTO is a risk factor for sudden death or severe cardiovascular events [1]. The factors inducing LVOTO during exercise stress testing are summarized in Table 2 [3]. One study has reported that, of all HCM patients, 37% of patients reveal LVOTO at rest (hypertrophic obstructive cardiomyopathy), 33% of patients have latent LVOTO induced by exercise stress testing, which is not observed at rest, and 30% of patients have true nonobstructive HCM in which no LVOTO is observed either at rest or during exercise stress testing [7]. Shah et al. reported that approximately two out of three symptomatic HCM patients with chest pain, those with shortness of breath, those with presyncope, who showed no LVOTO at rest, had latent LVOTO [8]. This emphasizes the importance of evaluating LVOTO during exercise stress echocardiography when any symptoms are present during exertion, even if LVOTO is not observed during echocardiography at rest. Echocardiographic findings reported to cause LVOTO include hypertrophy of the basal interventricular septum, narrowing of LVOT (B2 cm), and a steep
J Echocardiogr Table 1 Recommendation for exercise echocardiography in hypertrophic cardiomyopathy Source: Elliott et al. [1] Recommendations
Class
Level
In all patients with HCM at initial evaluation, transthoracic 2D and Doppler echocardiography are recommended, at rest and during Valsalva maneuver in the sitting and semi-supine positions—and then on standing if no gradient is provoked
I
B
In symptomatic patients with a resting or provoked peak instantaneous LV outflow tract gradient \50 mmHg, 2D and Doppler echocardiography during exercise in the standing, sitting or semi-supine position is recommended to detect provocable LVOTO and exercise-induced mitral regurgitation
I
B
In asymptomatic patients with a resting or provoked peak instantaneous LV outflow tract gradient \50 mm Hg, 2D and Doppler echocardiography during exercise—in the standing, sitting, or semi-supine positions—may be considered when the presence of an LVOT gradient is relevant to lifestyle advice and decisions on medical treatment
IIb
C
Fig. 1 Latent left ventricular outflow tract obstruction (LVOTO). LVOTO is defined as not being observed at resting echocardiography but induced by exercise stress testing. 2D and Doppler echocardiography during a Valsalva maneuver, in the sitting and semi-supine Table 2 Factors contributing to dynamic left ventricular outflow tract obstruction Source: Otto [3]
positions and then on standing if no gradient is provoked, is recommended in all patients. Exercise stress echocardiography is performed in symptomatic patients when bedside manoeuvers fail to induce LVOTO C50 mmHg
Narrowing of left ventricular outflow tract Septal hypertrophy Anterior displacement of the mitral apparatus Anterior displacement of the papillary muscles Hydrodynamic forces (venturi and drag forces) causing systolic anterior motion Rapid early LV ejection Elongated mitral leaflets
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angle between the long axis of the left ventricle and the ejection flow (C35°) [9]. In contrast to exercise-induced LVOTO occurring in HCM patients, some studies have reported HCM in which LVOTO is alleviated by exercise stress testing. One report demonstrated that nine out of 38 HCM patients (24%) exhibited a paradoxical response; that is, LVOTO was alleviated by exercise stress testing and these patients had a low incidence of cardiovascular events [10]. It is difficult to observe this phenomenon after exercise stress testing using a treadmill because LVOTO often reappears after the test. To understand this phenomenon, LVOTO needs to be evaluated during exercise using an ergometer (Fig. 2). The procedures to alleviate LVOTO, such as a septal myectomy (Morrow procedure) and percutaneous transluminal septal myocardial ablation, are indicated for class I symptomatic patients with LVOTO at rest who are resistant to drug therapy. However, these procedures are also indicated for class I symptomatic cases with maximum peak LVOT gradient C50 mmHg during exercise stress testing
even if LVOTO is not observed at rest [1]. Exercise stress echocardiography is also useful for determining the postoperative effectiveness of these therapeutic procedures [3].
Fig. 2 A case of asymptomatic HCM with reduced LVOTO during exercise stress testing. The patient presented with a paradoxical response, i.e., a peak LVOT gradient of 100 mmHg at rest that decreased to 62 mmHg during peak exercise. The reduction in LVOTO was not observed in this patient during the evaluation
performed after exercise stress testing on a treadmill because it rapidly reappeared after the stress test was completed. Although highgrade LVOTO was observed at rest, to date, the patient’s clinical course has been improved without any symptoms of cardiac failure or arrhythmic events
123
MR MR in HCM patients is caused by SAM of the mitral valve or the abnormalities of the mitral complex (valve cusp, chorda tendineae, and papillary muscles). MR is reported to trigger dynamic changes (Fig. 3) influenced by the degree of LVOTO during exercise stress testing [11]. Exercise plays a primary role in dynamic LVOTO obstruction due to a hyperdynamic left ventricle with a small cavity and SAM of the mitral valve leaflet. SAM is possibly associated with MR. It may also be complicated by morphological abnormalities of the tissues forming the mitral complex in patients with HCM [12] and have no associations with the degree of LVOTO or the severity of MR in some cases [13]. MR must be assessed while
J Echocardiogr Fig. 3 Exercise-induced systolic anterior motion (SAM)—mitral regurgitation (MR) in HCM. Although SAM or LVOTO was not observed at rest and only mild MR was identified, SAM and LVOTO were induced during exercise stress testing and the MR increased dynamically. Right ventricular systolic pressure (RVSP) increased from 33 mmHg to 63 mmHg. These findings indicated exerciseinduced pulmonary hypertension
evaluating LVOTO during exercise stress echocardiography in HCM patients [1]. Since there are some difficulties to distinguish MR signals from LVOT blood flow signals, special caution is required during measurement. These signals can be distinguished according to the following facts: the MR velocity curve shows a sharp increase in velocity at early systole with the slope reflecting the rate of rise in LV pressure, whereas the LVOT velocity gradually increases during early systole with an abrupt increase in velocity in mid- to late-systole as obstruction worsens in conjunction with SAM. In addition, MR signals have a long duration, extend beyond the second heart sounds, and continue until the mitral valve opens. The flow velocity of MR is always higher than that of the LVOT [3]. LVOTO will be overestimated when a MR signal is misrecognized as a LVOT blood flow signal; therefore, extreme caution is required during evaluation.
Left ventricular wall motion abnormality Peteiro et al. performed exercise stress testing in 239 HCM patients and found ventricular asynergy during exercise stress testing in 19 patients (7.9%). They reported that left ventricular asynergy was an independent predictive factor for cardiac-related death and serious events, such as cardiac transplantation [14]. Reant et al. investigated prognoses in 115 HCM patients and demonstrated that, even though left ventricular ejection fraction was maintained during resting echocardiography, there were some cases with decreased global longitudinal strain during exercise and it predicted serious events [15]. Their study results suggested that any findings demonstrating latent ischemia might predict prognosis. Irrespective of the detection of LV wall motion abnormalities, clinical symptoms and examination findings suggesting myocardial ischemia, such as chest pain, chest discomfort, abnormal Q waves, and ST-T changes, are
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frequently observed in patients with HCM [16]. These are due to (1) hypertrophy of the coronary arteriolar media and intima layers and decreased vasodilatory reserve, (2) compression stenosis of the intramyocardial coronary vessels, particularly the septal branches triggered by the contracting myocardium, (3) decreased diastolic coronary artery flow caused by impaired left ventricular relaxation, (4) increased intraventricular pressure triggered by LVOTO, and (5) decreased capillary density caused by hypertrophy and restricted subendocardial myocardial perfusion. These findings suggest that the presence of ischemia in HCM patients should be associated with prognosis and an evaluation of wall motion be required during exercise stress echocardiography.
briefly asymptomatic clinical course, although, NYHA Class II dyspnea on effort was detected. Exercise stress echocardiography was then requested. No LVOTO, MR or wallmotion abnormalities were observed at rest or during exercise echocardiography. The indices of left ventricular diastolic function increased from 0.8 to 1.7 (E/A) and from 8.5 to 13.0 (E/e0 ). The estimated pulmonary artery systolic pressure increased from 18 to 55 mmHg. These findings indicated exercise-induced pulmonary hypertension. Patients with apical HCM are generally considered as having favorable prognoses, although some patients have reduced diastolic function reserve. These patients should be subject to conscientious follow-up observation. Conclusions
Diastolic function Our previous study has reported the importance of diastolic function reserve in HCM patients [17]. We performed exercise stress echocardiography and cardiopulmonary exercise testing in 33 HCM patients. Although there were no associations between the echocardiographic indicators at rest and exercise capacity, we could find a strong correlation between the early diastolic longitudinal strain rate (LSR) during exercise and exercise capacity. Particularly, the changes in the LSR (diastolic function reserve) were an independent prognostic factor for exercise capacity; thus, the LSR was useful for the prediction of exercise capacity during exercise stress echocardiography in HCM patients (Fig. 4). Figure 5 presents a case of apical HCM that we encountered at our hospital. The patient was a 66-year-old man. A detailed ECG examination resulted in apical HCM. He had a
Patients with HCM present a variety of clinical symptoms; some of them may cause sudden death. It is quite difficult to define that patients with HCM have good prognoses. The evaluation of the subjective symptoms and risk factors for sudden death in detail and the presence of subjective symptoms are required for decision-making in the treatment of these patients. Meanwhile, the subjective symptoms by their very nature are matters to be concerned. When these symptoms prevent decision-making, we recommend that exercise stress echocardiography be performed. There are a number of patients who are incidentally diagnosed as being asymptomatic in the outpatient department but they have remarkable dyspnea in their daily activities. ECG, blood pressure, heart rate, and exercise capacity should objectively be evaluated during exercise; that is, these measurements contribute to the understating of one’s status
Fig. 4 Relationship between left ventricular strain during exercise and exercise capacity (cited from [17]). A significant positive correlation between the LSRe during exercise and peak VO2 was observed
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J Echocardiogr Fig. 5 A patient with apical HCM complaining of exertional dyspnea. No LVOTO, MR, or wall-motion abnormalities were observed at rest, nor were these findings observed during exercise stress echocardiography. However, the echocardiographic indicators of left ventricular dilation increased from 0.8 to 1.7 (E/ A) and from 8.5 to 13.0 (E/e0 ); Right ventricular systolic pressure (RVSP) increased from 18 to 55 mmHg. These findings indicated exercise-induced pulmonary hypertension
on exertion. Most of the published reports concerning exercise stress echocardiography in HCM patients are the single-center studies and, to date, there is no standardized protocol. In the 2014 ESC HCM guidelines, exercise stress echocardiography is recommended for
class I patients. Since the importance of exercise stress echocardiography in HCM has been widely recognized, a multi-center study of exercise stress echocardiography is thus called for the standardization of the protocol in Japan.
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