Introduction

However, ischaemic heart disease is only one of the many diseases and conditions that can be assessed with SE. In recent years, SE has become an established method for the assessment of a wide spectrum of challenging clinical conditions, including systolic or diastolic heart failure, non-ischaemic cardiomyopathy, valvular heart disease, pulmonary hypertension (PH), athletes’ hearts, congenital heart disease (CHD), and heart transplantation. Due to the growing body of evidence supporting the use of SE beyond the evaluation of ischaemia, its increasing implementation in many echocardiography laboratories and its recognized diagnostic and prognostic value, it has thus become essential to establish guidance for its applications and performance. This paper provides recommendations for the clinical applications of SE to non-ischaemic heart disease. When clinically indicated, ischaemia can also be assessed in conjunction with assessments of non-ischaemic conditions, but it is not the focus of this document.

Stress Echocardiography Methods

SE provides a dynamic evaluation of myocardial structure and function under conditions of physiological (exercise) or pharmacological (inotrope, vasodilator) stress. The images obtained during SE permit matching symptoms with cardiac involvement. SE can unmask structural/functional abnormalities, which—although occult in the resting or static state—may occur under conditions of activity or stress, and lead to wall motion abnormalities, valvular dysfunction, or other haemodynamic abnormalities.

Exercise is the test of choice for most applications. As a general rule, any patient capable of physical exercise should be tested with an exercise modality, as this preserves the integrity of the electromechanical response and provides valuable information regarding functional status. Performing echocardiography at the time of exercise also allows links to be drawn among symptoms, cardiovascular workload, wall motion abnormalities, and haemodynamic responses, such as pulmonary pressure and transvalvular flows and gradients. Exercise echocardiography can be performed using either a treadmill or bicycle ergometer protocol. Semi-supine bicycle exercise is, however, technically easier than upright bicycle or treadmill exercise, especially when multiple stress parameters are assessed at the peak level of exercise.

Pharmacological stress does not replicate the complex haemodynamic and neurohormonal changes triggered by exercise. This includes psychological motivation and the response to exercise of the central and peripheral nervous systems, lungs and pulmonary circulation, right ventricle (RV) and left ventricle (LV), myocardium, valves, coronary circulation, peripheral circulation, and skeletal muscle. Dobutamine is the preferred alternative modality for the evaluation of contractile and flow reserve. Vasodilator SE is especially convenient for combined assessment of wall motion and coronary flow reserve, which may be indicated in dilated non-ischaemic cardiomyopathy and hypertrophic cardiomyopathy (HCM).

A flexible use of exercise, dobutamine, and vasodilator stresses maximizes versatility, avoids specific contraindications of each, and makes it possible to tailor the appropriate test to the individual patient ( Table 1 ).

Stress Echocardiography Methods

SE provides a dynamic evaluation of myocardial structure and function under conditions of physiological (exercise) or pharmacological (inotrope, vasodilator) stress. The images obtained during SE permit matching symptoms with cardiac involvement. SE can unmask structural/functional abnormalities, which—although occult in the resting or static state—may occur under conditions of activity or stress, and lead to wall motion abnormalities, valvular dysfunction, or other haemodynamic abnormalities.

Exercise is the test of choice for most applications. As a general rule, any patient capable of physical exercise should be tested with an exercise modality, as this preserves the integrity of the electromechanical response and provides valuable information regarding functional status. Performing echocardiography at the time of exercise also allows links to be drawn among symptoms, cardiovascular workload, wall motion abnormalities, and haemodynamic responses, such as pulmonary pressure and transvalvular flows and gradients. Exercise echocardiography can be performed using either a treadmill or bicycle ergometer protocol. Semi-supine bicycle exercise is, however, technically easier than upright bicycle or treadmill exercise, especially when multiple stress parameters are assessed at the peak level of exercise.

Pharmacological stress does not replicate the complex haemodynamic and neurohormonal changes triggered by exercise. This includes psychological motivation and the response to exercise of the central and peripheral nervous systems, lungs and pulmonary circulation, right ventricle (RV) and left ventricle (LV), myocardium, valves, coronary circulation, peripheral circulation, and skeletal muscle. Dobutamine is the preferred alternative modality for the evaluation of contractile and flow reserve. Vasodilator SE is especially convenient for combined assessment of wall motion and coronary flow reserve, which may be indicated in dilated non-ischaemic cardiomyopathy and hypertrophic cardiomyopathy (HCM).

A flexible use of exercise, dobutamine, and vasodilator stresses maximizes versatility, avoids specific contraindications of each, and makes it possible to tailor the appropriate test to the individual patient ( Table 1 ).

Haemodynamic Effects of Myocardial Stressors

All SE stressors have associated haemodynamic effects. As a common outcome, they result in a myocardial supply/demand mismatch and may induce ischaemia in the presence of a reduction in coronary flow reserve, due to epicardial stenoses, LV hypertrophy, or microvascular disease. Exercise and inotropic stressors normally provoke a generalized increase of regional wall motion and thickening, with an increment of ejection fraction (EF) mainly caused by a reduction of systolic dimensions.

Stress Echocardiography Protocols

Bicycle

Bicycle ergometer exercise echocardiography may be performed with the patient upright or on a special semi-recumbent bicycle, which may have left lateral tilt to facilitate apical imaging. The patient pedals against an increasing workload at a constant cadence ( Figure 1 ). The workload is escalated in a stepwise fashion while imaging is performed. Successful bicycle stress testing requires the patient’s cooperation to maintain the correct cadence and coordination to perform the pedalling action. Causes of test cessation and definition of abnormal stress test are listed in Figure 2 .

Exercise echocardiography protocol and parameters that can be assessed at each stage. bpm, beats per minute; LV , left ventricle; LVOT , LV outflow tract; MR , mitral regurgitation; E / e ′, ratio of early transmitral diastolic velocity to early TDI velocity of the mitral annulus; RWM , regional wall motion; RV , right ventricle; SPAP , systolic pulmonary artery pressure; W , watts; rpm , rotations per minute. Valve refers to aortic or mitral valve.

Diagnostic end-points, causes of test cessation and definition of abnormal stress test. Asterisk indicates specific targeted features relates to cut-off values associated with poor outcome in defined population (i.e. >50 mmHg intraventricular obstruction). NS , non-sustained; SVT , sustained ventricular tachycardia.

Dobutamine

For detection of inotropic response in HF patients, stages of 5 min are used, starting from 5 up to 20 μg/kg/min ( Figure 3 ). To fully recruit the inotropic reserve in patients with HF and under β-blocker therapy, doses up to 40 μg/kg/min may be required. Atropine coadministration is associated with higher rate of complications in those with a history of neuropsychiatric symptoms, reduced LV function, or small body habitus. In assessment of the patient with possible severe aortic valve stenosis, the maximal dose is usually 20 μg/kg/min; higher doses are less safe and probably unnecessary. The dobutamine infusion is started as usual at 5 μg/kg/min but titrated upward in steps of 2.5–5 μg/kg/min every 5–8 min. After each increment in dobutamine dose, a period of 2–3 min before starting the image acquisition will allow the haemodynamic response to develop.

Dobutamine echocardiography protocol. A low-dose test is recommended in patients with low-flow, low-gradient aortic stenosis and reduced LVEF. In patients with heart failure that are receiving beta-blocker therapy, high doses up to 40 μg/kg/min (without atropine) of dobutamine are often required. AVA , aortic valve area; LV , left ventricle; LVOT , LV outflow tract; RWM , regional wall motion; SV , stroke volume. Valve refers to aortic or mitral valve.

Diastolic Stress Echocardiography

The importance of diastolic dysfunction for symptoms such as shortness of breath, exertional fatigue, or poor exercise capacity has been increasingly recognized, and diastolic dysfunction is considered to be the main cause in ∼40% of patients presenting with clinical HF.

Diastolic SE generally refers to the use of exercise Doppler echocardiography to detect impaired LV diastolic function reserve and the resulting increase in LV filling pressures in patients with unexplained dyspnoea or subclinical diastolic dysfunction (e.g. diabetic cardiomyopathy, hypertensive patients). Nonetheless, it is mainly of value in patients with suspected HF with preserved LVEF and borderline diastolic abnormalities at rest. Figure 4 summarizes when diastolic SE should be considered in clinical practice. Figures 5 and 6 show examples of diastolic stress results.

Diastolic SE performed for the assessment of dyspnoea, breathlessness, or exertional fatigue. Asterik indicates criteria used to diagnose heart failure with preserved LV EF. CO , cardiac output; Exer , exercise; LVOTO , LV outflow tract obstruction; MR , mitral regurgitation; RWMA , regional wall motion abnormality; SV , stroke volume; E , early transmitral diastolic velocity; e ′, early TDI velocity of the mitral annulus; SPAP , systolic pulmonary artery pressure; PH , pulmonary hypertension; TR , tricuspid regurgitation; HFeEF , heart failure with preserved LVEF.

Mitral flow and annular velocity at rest, during supine bicycle exercise and recovery in a 71-year-old man with exertional dyspnoea. At baseline, mitral inflow pattern revealed abnormal relaxation with normal range of E / e ′. However, mitral inflow pattern dramatically changed after 5 min of supine bicycle exercise from normal to restrictive physiology with significantly elevated E / e ′. The variable e ′ refers to septal velocities.

Mitral flow and annular velocity at rest, during supine bicycle exercise, and in recovery in a 56-year-old woman with hypertension and exertional dyspnoea. Because of tachycardia even with mild exercise, E / e ′ could not be measured at 50 W of exercise. Note that E / e ′ was significantly elevated even after cessation of exercise and was higher than at rest and during exercise.

Exercise using a supine bicycle is the recommended modality for diastolic SE as it allows the acquisition of Doppler recordings throughout the test and the non-invasive assessment of exercise diastolic function reserve. Treadmill exercise SE is an alternative as diastolic abnormalities may persist after exercise. Preload augmentation by passive leg raise might also represent a non-exercise alternative since it provides additional information identifying patients with exercise-induced LV filling pressure elevation and lower exercise capacity.

A diastolic SE protocol can be used as a stand-alone test or it can be added to the assessment of regional wall motion abnormalities. Mitral E, A, E/A (1–2 mm sample volume pulsed wave Doppler placed at the tip of mitral valve), e ′ (5- to 10-mm sample volume pulsed wave tissue Doppler, septal and/or lateral mitral annulus, Nyquist limit at 15–20 cm/s with adjustment of gain and filter), E / e ′, and SPAP should be recorded at baseline, at low-level exercise, and during the recovery period. The variables E and e ′ are usually recorded at 100–110 bpm, when E and A waves are not yet fused. Although less evidence is available, post-exercise assessment during the recovery period can be performed, especially when there has been an abrupt increase in heart rate with low level of exercise. Recordings are obtained using the apical four-chamber view and a total of 5–10 cardiac cycles should be recorded. For the patient unable to exercise, diastolic function can be assessed during passive leg raise. The patient’s legs are passively elevated for 3 min, and similar Doppler-echocardiographic parameters are recorded. The limitations of E / e ′ as non-invasive estimates of LV filling pressures as assessed by resting echocardiography are also applicable for diastolic SE.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is a heterogeneous inherited cardiomyopathy with variable phenotypic expression. Although some patients are asymptomatic, others have HF, and some present with sudden death. Disease progression is often due to diastolic dysfunction, MR, and LVOT obstruction (LVOTO).

Exercise SE is safe and commonly used to assess inducible LVOTO, especially in patients with equivocal symptoms, to determine functional capacity prior to a corrective therapeutic procedure, and for individual risk stratification ( Figure 7 ). In the ESC guidelines, exercise echocardiography is recommended in symptomatic patients if bedside manoeuvres fail to induce LVOTO ≥ 50 mmHg and is rated as class IIa, level of evidence B in the ACC/AHA guidelines. Post-prandial gradients are higher than those performed in the fasting state and pre-treatment with β-blockers is known to reduce the incidence and severity of exercise-induced LVOTO.

Example of dynamic intraventricular obstruction during exercise echocardiography in a dyspneic patient with HCM. Top : Increase in left ventricular outflow tract velocity and gradient associated with a marked flow acceleration ( red arrow ) (note the laminar flow at rest ( yellow arrow )). Note the greater increase in intraventricular gradient after exercise due to the decrease in venous return. Bottom : Systolic anterior motion of the mitral valve identified on 2D ( left ) and M-mode ( right ) echocardiography ( white arrows ).

Approximately one-third of patients have resting systolic anterior motion of the mitral valve leaflets that results in LVOTO, while another third have latent obstruction unmasked only during manoeuvres that change loading conditions (standing, Valsalva, nitrates, exercise) and LV contractility. Of note, pharmacological provocation with dobutamine is not recommended, as it is not physiological, can be poorly tolerated, and can induce LVOTO even in normal subjects. However, dobutamine or isoproterenol is used routinely in the operating room both pre- and post bypass to evaluate septal contact of the mitral valve leaflets and to guide the extent of the myectomy and surgical management of the mitral valve, which may require plication. Often, amyl nitrite may not reproduce exercise-induced gradients.

Exercise Doppler echocardiography can be performed in a standing, sitting, or semi-supine position. The echocardiographic parameters are assessed during exercise and at the beginning of the recovery period, when preload decreases. In patients with equivocal symptoms, if exercise SE does not produce LVOTO gradients, assessment for post-exercise standing gradients should be considered. An upright position after exercise causes a greater decrease in preload. Assessment of post-prandial exercise standing gradient may also be considered. In patients already under β-blockers, treatment should not be withdrawn prior to exercise SE.

The following parameters can be evaluated during the test, especially during semi-supine exercise: blood pressure, symptoms, heart rate, electrocardiographic changes, LVOTO, LV systolic/diastolic ( E / e ′) function, MR, and SPAP ( Figures 8–10 ). Post-exercise testing mainly focuses on LVOTO induction, SPAP, and diastolic parameters. Effort should be made to distinguish the subvalvular gradient from the MR jet. A limited exercise capacity, an abnormal blood pressure response (hypotensive or blunted response), significant ST-depression, inducible wall motion abnormalities, blunted coronary flow reserve (dipyridamole test), exercise LVOTO (>50 mmHg), and blunted systolic function reserve are all parameters of worse prognosis. Dynamic increase in MR, often in relation to systolic anterior motion of the mitral valve, blunted changes in e ′ (no diastolic reserve), increase in E / e ′, and PH at exercise are all markers of poor exercise tolerance. 2D strain imaging of LV function can be accurately performed at 100–120 bpm and is more sensitive to identify subtle changes in intrinsic myocardial function. A blunted increase in global longitudinal strain (limited contractile reserve) favours diagnosis of HCM rather than athletes’ heart. Intriguingly, some patients can display a paradoxical decrease in LVOTO during exercise, which is associated with a more favourable outcome and suggests alternative reasons for dyspnoea.

Significant increase in mitral regurgitation during exercise echocardiography (mild at rest and severe at exercise) in a patient with HCM.

Dyspneic patient with HCM, increased dynamic intraventricular obstruction ( top ) and left ventricular filling pressure ( bottom , E / e ′) during exercise echocardiography.

Breathless patient with HCM and chronic obstructive pulmonary disease. Exercise echocardiography reveals the presence of systolic (increase in global longitudinal strain [GLS]) and diastolic (increase in e ′) reserve without significant increase in E / e ′ (left ventricular filling pressure). These data suggest that the symptoms are mainly due to the pulmonary disease.

Heart Failure with Depressed LV Systolic Function and Non-ischaemic Cardiomyopathy

Non-ischaemic cardiomyopathy is relatively common in patients presenting with HF and is associated with a high mortality rate. In these patients, increased circulating catecholamines are accompanied by a decreased density and downregulation of β-receptors, which is associated with poor response to β adrenergic blocking agents and worse outcomes. Studies have shown that myocardial contractile response to exogenous catecholamines has important prognostic implications.

In early stages of heart failure, when resting LVEF is still preserved, a blunted contractile reserve can identify incipient, pre-clinical myocardial damage. Such a response may be used in detection of early chemotherapy-induced cardiotoxicity, thalassemia, and hypertensive and diabetic cardiomyopathy. In the overt stage of non-ischaemic cardiomyopathy, residual myocardial contractile reserve as assessed by SE can assist to distinguish ischaemic from non-ischaemic disease, for outcome assessment, and aid to clinical decision making.

Although dobutamine SE is most often used, exercise SE can also be performed. Several protocols including low-dose (10 μg/kg/min) to high-dose (40 μg/kg/min) dobutamine SE have been used to evaluate contractile reserve, changes in LV volumes and EF. There is, however, no consensus on the optimal dobutamine protocol to evaluate patients with non-ischaemic cardiomyopathy. One of the advantages of high-dose compared with low-dose dobutamine in this cohort of patients is that the high dose is more likely to invoke a contractile response especially if the patients are on β-blockers, thus decreasing the chances of a false-negative finding. However, high-dose dobutamine is more likely to cause significant arrhythmias.

Alternatively, exercise SE protocols may be used, sometimes with longer stages to permit acquisition of more data at each stage, including systolic and diastolic reserve, SPAP, dynamic MR, or B-lines ( Figure 11 ). B-lines or lung comets are discrete, laser-like, vertical, hyperechoic images that arise from the pleural line, extend to the bottom of the screen without fading, and move synchronously with respiration.

Lung ultrasound (third right intercostal space) at rest ( left upper panel ) and immediately after exercise ( left lower panel ). On the right panels, the schematic drawing showing normal, parallel, horizontal A-lines at rest ( right upper panel ), and three vertical B-lines ( arrows ) departing from the pleural line after exercise ( right lower panel ). The exercise-induced appearance of B-lines (also called ultrasound lung comets, ULC) reflects the acute increase of extravascular lung water. ULC presence is frequently associated with elevated PCWP and/or reduced EF.

Dipyridamole SE is rarely used to assess contractile reserve, but may be useful in patients on β-blockers, and is associated with less arrhythmias.

In patients with either preserved or reduced LVEF, the absence of contractile reserve is often associated with limited coronary flow reserve. It is a marker of latent LV systolic dysfunction and subclinical cardiomyopathy.

In dilated non-ischaemic cardiomyopathy, patients with significant improvement in their wall motion score index and LVEF during dobutamine infusion have a better survival rate, fewer hospitalizations for HF, and an increase in the LVEF during follow-up. Alternatively, dobutamine SE can be used in patients with HF with ambulation difficulties. Patients with inotropic contractile reserve respond better to β-blockers. The presence of inotropic contractile reserve was also associated with a decrease in the need for cardiac transplantation and correlates inversely with the extent of interstitial fibrosis and scarred myocardium. These findings have also been extended in specific aetiology of cardiomyopathy, including in peripartum and in HIV cardiomyopathy, where the presence of inotropic contractile reserve correlates with subsequent recovery of LV function at follow-up and also better outcomes. When the purpose of the dobutamine SE is to seek for LV contractile reserve and not myocardial ischaemia, atropine is not adiministered. In patients with non-ischaemic cardiomyopathy, blunted coronary flow reserve or the absence of contractile reserve during dipyridamole test is also a marker of poor prognosis.

In both patients with preserved or reduced LVEF, the presence and the amount of B-lines (lung comets) likely correlate with the estimated LV filling pressure and the presence of pulmonary interstitial edema. The demonstration of B-lines during exercise SE seems a feasible way for demonstrating that exertional dyspnoea is related to pulmonary congestion.

Cardiac Resynchronization Therapy

Several studies have shown a direct relationship between the presence of inotropic contractile reserve as assessed by low-dose dobutamine SE and improvement in ventricular function after cardiac resynchronization therapy. During dobutamine infusion, an increase of LVEF by ≥7.5% identified responders to cardiac resynchronization therapy. Furthermore, patients are more likely to be non-responders to cardiac resynchronization therapy if the LV pacing lead is placed in the region of no contractile reserve (scarred myocardium). The presence of inotropic contractile reserve during dobutamine SE also has incremental but lower predictive power than echocardiographic mechanical dyssynchrony parameters such as septal flash ( Figure 12 ). The degree of response (improvement of EF during dobutamine infusion) correlates directly with the number of segments demonstrating inotropic contractile reserve.

Patient with idiopathic cardiomyopathy and limited exercise capacity. (A–C) Rest evaluation; (D–F) exercise echocardiography results. From rest to exercise, there is an increase in mitral regurgitation severity ( A and E ) and in left ventricular dyssynchrony (B–F) . (A and D) increase in effective regurgitant orifice area (EROA) during test. (B and F) Bulls-eye figures of longitudinal peak systolic strain values in the LV. From rest to exercise, global strain increases (−6.3% to −10.4%) indicating the presence of contractile reserve. During exercise, there is a significant dyssynchrony between the infero-lateral wall and the anteroseptum wall (regional strain color-coded changes from orange to blue). (C and F) M-Mode echocardiogram showing the occurrence of a septal flash (rapid inward motion of the septum within the isovolumic contraction period) at exercise. SPWD, septal posterior wall motion delay.

Native Valve Disease

The clinical indications for SE in native valve disease can be classified into three categories: severe valve disease without symptoms, non-severe valve disease with symptoms, and valve disease with low flow. In all cases, the purpose of the test is to identify the patients in need of intervention, namely those patients with severe valve disease and symptoms, LV systolic dysfunction, or other haemodynamic consequences ( Figure 13 ). Therefore, in severe valve disease without symptoms the main aim of the test is to elicit symptoms, which may not be otherwise appreciated because of sedentary lifestyle. Additionally, the haemodynamic consequences of exertion in the patient with severe valve disease, such as exercise-induced hypotension or arrhythmia, may be uncovered. In non-severe valve disease with symptoms, the main aim of the test is to question whether the valve disease is actually severe, re-grading the severity based on stress-induced changes or a potential dynamic component. In valve disease with low flow, the aim of the test is to determine whether the valve disease is severe based on flow-dependent changes in severity parameters with stress.

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