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. 2018 Nov 24;41(12):1600–1610. doi: 10.1002/clc.23094

Stress ECHO beyond coronary artery disease. Is it the holy grail of cardiovascular imaging?

Constantina Aggeli 1, Kali Polytarchou 1,2,✉, Dimitrios Varvarousis 3, Stellios Kastellanos 1, Dimitrios Tousoulis 1
PMCID: PMC6489791  PMID: 30315566

Abstract

Stress echocardiography (SE) is a very useful method in clinical practice, because it offers important information of both the patient's functional status and hemodynamic changes during stress. Therefore, SE provides strong diagnostic and prognostic data in a wide spectrum of cardiovascular diseases. This review summarizes the clinical applications of SE in conditions beyond coronary artery disease (CAD) and highlights practical recommendations and key issues for each condition that need further investigation. SE is an established method for the evaluation of symptomatic and asymptomatic patients with valvular heart disease (VHD) and cardiomyopathies, and provides important information regarding prognosis and management of patients with congenital heart disease, pulmonary hypertension or diastolic dysfunction. Moreover, when one or multiple VHD and cardiomyopathy or CAD coexist in one patient, SE is a very useful clinical tool for the evaluation of etiology and symptomatology.

Keywords: cardiomyopathy, heart failure, mitral stenosis, pulmonary hypertension, stress echocardiography, valvular heart disease

1. INTRODUCTION

Stress echocardiography (SE) is a well‐established tool for noninvasive evaluation of patients with coronary artery disease (CAD) and ischemic cardiomyopathy.1 Furthermore, it has useful clinical applications and offers strong prognostic data in a wide spectrum of pathological conditions, including valvular heart disease (VHD), pulmonary hypertension (PH), nonischemic cardiomyopathy and congenital heart disease (CHD).

Recently, the European Association of Cardiovascular Imaging and the American Society of Echocardiography have published recommendations for SE in nonischemic cardiac disease demonstrating different parameters for each disease, from asymptomatic severe aortic stenosis (AS) to the forgotten tricuspid valve regurgitation (TR).2 However, it is crucial for the physician to know the clinical question and select the ideal SE protocol for each patient. The most common questions pertain to the morphological characteristics as well as the hemodynamic behavior of a native or prosthetic valve. Furthermore, myocardial function, chamber dilation, and the function of the aorta or pneumonic artery are crucial complementary parameters. Most of these parameters are dependent on the presence of hemodynamically severe CAD.

This review summarizes the clinical applications of SE in conditions beyond CAD and highlights practical recommendations.

1.1. Stress echocardiography methods and hemodynamic effects

Exercise and pharmacological stress are the two main methods used in SE, each with different effects on cardiovascular parameters. During exercise with treadmill or bicycle, heart rate increases 2‐to 3‐fold, systolic blood pressure (BP) about 50% and the contractility 3‐ to 4‐fold, whereas the systemic vascular resistance decreases, resulting in increase of stroke volume (SV) and myocardial oxygen consumption.1, 2 Although treadmill test increases mainly the heart rate, while semi‐tilted bicycle increases mainly the BP, in the end, the double product is similar between both exercise protocols (Figure S1, Supporting Information).2

Dobutamine is the agent mostly used for pharmacological stress. Through β‐1 receptors activation, it increases heart rate 2‐ to 3‐fold, systolic BP 2‐fold and contractility 4‐fold.1, 2 At higher doses, BP is slightly decreased, through β‐2 receptors activation. Dobutamine, because of its positive inotropic effect on the myocardium, is the preferred stress method for the evaluation of contractility reserve.

During a SE study, data are recorded and saved for further analysis from the senior physician. For this purpose, it is crucial to evaluate the patient's profile to select the proper protocol and furthermore to record the appropriate parameters leading to accurate diagnosis and prognosis.

In nonischemic cardiac conditions, exercise is the preferred stress method and therefore, this review focuses mainly on exercise protocols. It is very important for these patients to exclude CAD before proceeding to SE. Coronary flow velocity reserve has significant prognostic value in most of these cardiac conditions and a concomitant evaluation of coronary and contractile reserve (CR) would add significant information. However, this is very difficult technically. Dobutamine is the ideal agent for the assessment of CR, although coronary flow reserve can additionally be assessed. Vasodilators (dipyridamole, adenosine, and regadenoson) are the agents of choice for the evaluation of coronary flow reserve. The combination of both dobutamine and a vasodilator might be the ideal stress protocol for concomitant evaluation of coronary flow and CR. Moreover, exercise could be an alternative stress protocol for this purpose.

2. NATIVE VALVULAR HEART DISEASE

2.1. Aortic stenosis

The role of SE in AS is well established. The left ventricle (LV) of a patient with AS has to manage the increased aortic valve resistance and the increased vascular resistance. Subsequently, there are several questions that need to be answered. Which is the valvular load? Is there a way to differentiate it from the vascular load? Is there any LV‐CR? Which is the role of mitral regurgitation (MR) for the specific patient? Is there any right ventricular (RV) CR, in cases with concomitant RV dysfunction and severe TR? Current European Society of Cardiology (ESC) and American Heart Association (AHA)/American College of Cardiology (ACC) guidelines present the steps for evaluation of a patient with AS; however, there are still remaining issues that need to be resolved.3, 4

Guidelines recommend the performance of SE in asymptomatic patients with severe AS, in order to unmask symptoms and evaluate low‐flow low‐gradient (LF‐LG) AS with reduced left ventricular ejection fraction (LVEF).3, 4, 5 Exercise stress test in semi‐tilted bicycle is preferred over pharmacological stress. Exercise testing in asymptomatic patients with severe AS is safe, if performed in an experienced center under close monitoring for symptom occurrence and changes in BP or cardiac rhythm. The rise of mean pressure gradient (mean PG) ≥18 mm Hg and of systolic pulmonary artery pressure (PASP) >60 mm Hg, the drop of BP and the onset of symptoms in asymptomatic patients with severe AS constitute negative prognostic factors.2 In the 2012 ESC guidelines, a change in mean transaortic PG and PASP constituted an indication for aortic valve replacement (AVR). However, this was taken out from the current ESC guidelines, and so, close monitoring but not AVR is recommended for asymptomatic patients with severe AS. Available clinical studies have provided controversial data, because mean transaortic PG increases in those patients during exercise, because of a rise in SV, and this has not been directly linked to a negative outcome.4 In addition, the echocardiographic estimation of PASP is not very accurate, and therefore, the invasive evaluation is recommended instead. Although those parameters might have a prognostic value, this needs to be further studied.

In patients with LF‐LG AS with reduced EF [defined as aortic valve area (AVA) <1.0 cm2, mean PG < 40 mm Hg and EF < 50%], dobutamine SE is the best method for both the evaluation of LV‐CR and for the differentiation of true‐severe from pseudo‐severe AS (Figure 1).6 In general, flow rate is the most important factor, not only in patients with reduced EF but also with preserved EF, and should always be evaluated. Current guidelines suggest the evaluation of indexed SV (SVi, SV/body surface area) instead of the evaluation of flow rate.4, 7 If SVi is <35 mL/m2, then stress test is needed for the evaluation of AVA. If this is not achievable or when there is disconcordance between AVA and PG, then some investigators suggest the calculation of AVA projected, defined as:

Figure 1.

Figure 1

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A patient with low‐flow, low‐gradient (LF‐LG) aortic stenosis (AS) undergoing dobutamine stress echocardiography (SE) for the evaluation of AS severity. At rest (A, B), aortic valve area is estimated at 0.5 cm2 and left ventricular ejection fraction at 30%. During low‐dose dobutamine SE (C, D), stroke volume increases by 20%, indicating presence of contractile reserve. Valve area during stress remains unchanged at 0.5 cm2, indicating true severe LF‐LG AS

AVAproj   =  AVArest + (ΔAVA/ΔQ) × (250 − Qrest).

(AVArest and Qrest: AVA and mean transvalvural flow rate at rest, ΔAVA and ΔQ: absolute changes in AVA and flow rate measured during SE).7

True severe AS is suggested with AVAproj <1.0 cm2. AHA/ACC guidelines recommend AVR in patients with true severe LF‐LG AS with reduced EF and CR (class IIa), whereas in patients without LV‐CR, there is a less strong indication for AVR (class IIb).3 According to the current ESC guidelines, AVR is recommended in patients with true severe LF‐LG AS with reduced EF and CR (class I) and should be considered in symptomatic patients with LF‐LG AS and reduced EF without CR (class IIa).4

In patients with LF‐LG AS with preserved EF (defined as AVA < 1.0 cm2, AVA indexed <0.6 cm2, mean PG < 40 mm Hg and EF >50% with SVi < 35 mL/m2), dobutamine SE is not a well‐established method and semi‐tilted bicycle exercise should be preferred for the evaluation of stenosis severity.7 Furthermore, if SE is inconclusive, aortic valve calcium score by multidetector computed tomography is a useful prognostic factor in identifying true severe AS. Symptomatic patients with LF‐LG with preserved EF and true severe AS have a class IIa indication for AVR.3, 4 Figure 2 presents a proposed algorithm for the diagnostic evaluation of LF‐LG AS.

Figure 2.

Figure 2

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Algorithm for the diagnostic evaluation and management of patients with low transaortic pressure gradient aortic stenosis. AVA: aortic valve area; AVAi: AVA indexed; AoV: aortic valve; AVAproj: AVA projected; LVEF: left ventricular ejection fraction; LF‐LG: low‐flow, low‐gradient; MDCT: multidetector computed tomography; NF‐LG: normal‐flow, low‐gradient; PG: pressure gradient; SE: stress echocardiography; SVi: stroke volume indexed; Δ: absolute difference

Beside the assessment of stenosis severity, one should never forget to evaluate the patient for regional wall motion abnormalities (WMA). Furthermore, the occurrence of exercise induced pulmonary hypertension (EIPH) seems to be a negative prognostic factor in asymptomatic AS patients.

2.2. Aortic regurgitation

SE is not a useful tool for the evaluation of the severity of aortic regurgitation (AR), since regurgitant volume decreases with the increase of the heart rate during stress. SE is recommended in symptomatic patients with moderate to severe AR, to reveal other possible causes of symptoms. Semi‐tilted bicycle is the preferred method of exercise. SE contributes in the early identification of latent LV dysfunction.5 Parameters that should be assessed during stress are peak mitral annulus systolic tissue velocity (S′), Δ in LV end‐systolic volume, Δ in LV end‐systolic and end‐diastolic dimensions, Δ in LVEF and tricuspid annular plane systolic excursion (TAPSE).8

Failure of these to increase during stress testing indicates latent LV dysfunction and these patients should be followed‐up very closely for early AVR. Moreover, they all constitute prognostic factors for suboptimal LV remodeling post‐operatively.9

In patients with depressed LV function, dobutamine SE should be an alternative technique to evaluate the LV‐CR. Presence of CR predicts recovery of LV systolic function. On the other hand, absence of LV‐CR indicates the presence of extended myocardial fibrosis and probably irreversibly low LVEF. Because LVEF is load‐dependent, global longitudinal strain (GLS) during stress may be more accurate to assess LV‐CR.

2.3. Mitral stenosis

Clinically significant mitral stenosis (MS) is defined as mitral valve area (MVA) < 1.5 cm2.3, 4 SE is indicated in asymptomatic patients with severe MS, to reveal symptoms, and in symptomatic patients with moderate MS. Exercise SE is preferred at baseline, low and peak workload, although dobutamine at baseline, low and peak dose could be used in patients unable to exercise.2

MS is characterized as severe after stress testing with the occurrence of symptoms, increase in transmitral mean PG >15 mm Hg on exertion or > 18 mm Hg with dobutamine infusion and an increase in PASP>60 mm Hg.2 Because PASP is age‐dependent, some investigators suggest the increase in relative PASP>90% at 60 W workload as a more sensitive marker.10 However, both transmitral mean PG and the increase in PASP during exercise depend on atrioventricular compliance. Patients with low atrioventricular compliance (<4 mL/mm Hg) have more frequently dyspnea, lower functional capacity, and greater rise in PASP during exertion.10

Furthermore, calculation of MVA using pressure half time (PHT) or the continuity equation seems to be flow dependent. Low atrial or (more frequently) ventricular compliance may lead to overestimation of MVA using PHT.11 Concomitant AR or left heart failure (HF) may lead to rapid increase in end‐diastolic LV pressure, resulting in low transmitral mean PG, despite the existence of true severe MS. This condition could represent “low‐flow, low‐gradient” severe MS (Figure 3). In this case, exercise SE may add important clinical information for the evaluation of MS. In addition, the estimation of mitral valve resistance (MVRes) during stress might be a useful parameter for the assessment of the severity and the symptomatology of patients with moderate MS.11 MVRes seems to be flow‐independent and is calculated as: MVRes = mean transmitral PG/[(CSALVOT × VTILVOT)/DFT], where CSA means cross‐sectional area, LVOT left ventricular outflow tract and DFT diastolic filling time.

Figure 3.

Figure 3

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Stress echocardiography with semi‐tilted bicycle in a mildly symptomatic patient with mitral stenosis (MS) of rheumatic origin and moderate reduced left ventricular ejection fraction 45%. At rest (A, B), the mean transmitral pressure gradient is estimated at 8 mm Hg and systolic pulmonary artery pressure at 49 mm Hg. During stress (C, D), the patient becomes symptomatic and mean gradient increases to 12 mm Hg. Mitral valve area is estimated with 3D echocardiography during stress at 0.57 cm2, confirming the severity of MS

Again, as in AS evaluation, it is very important to evaluate the whole load that the left atrium (LA) should manage, consisting of the MVRes and the LV high filling pressure. Moreover, the variation of transvalvular gradient could be an alternative way to assess left atrial contractile function and reserve. This variation could be helpful in estimating mitral valvulopathy in patients with atrial fibrillation (AF).

2.4. Mitral regurgitation

Exercise SE, preferably with semi‐tilted bicycle, is the recommended method for the evaluation of MR, since dobutamine often decreases regurgitation and should only be used for the assessment of suspected inducible myocardial ischemia and LV‐CR.2 The major problem is that, frequently, many factors contribute to the mechanism of MR. Consequently, classification of MR as primary or secondary is often difficult. The cutoff values of MR regurgitant volume and area constitute an area of confusion and contradiction in European and American guidelines.3, 4

2.4.1. Primary MR

Asymptomatic patients with severe degenerative MR and symptomatic patients with moderate MR, should undergo exercise SE for the assessment of symptoms, severity of MR, LV‐CR, and for risk stratification.2, 4 SE may identify patients at higher risk who may benefit from early surgery, before the occurrence of symptoms.10, 12

Parameters that should be evaluated are CR estimated with Δ in LVEF or GLS during stress, LV end‐systolic and end‐diastolic dimensions, TAPSE for evaluation of RV‐CR, early diastolic transmitral flow velocity/early diastolic mitral annular tissue Doppler velocity (E/e′), estimation of proximal isovelocity surface area (PISA) and vena contracta (VC), MR jet with continuous wave (CW) Doppler, for the quantification of regurgitant volume and regurgitant orifice area (ROA), and TR jet with CW Doppler for estimation of PASP and EIPH.2, 10, 13 These parameters should be assessed at a heart rate of ~95 to 105/min.

Negative prognostic factors include increase in MR severity (>1grade), EIPH (PASP>60 mm Hg), absence of LV‐CR and TAPSE<19 mm.2, 10 Current ESC guidelines excluded exercise‐induced PASP>60 mm Hg as an indication for MVR, although they recognize the significant prognostic value of this parameter. As mentioned before, PASP is age‐dependent and the cutoff value of 60 mm Hg is low, since many elderly people may physiologically have PASP >60 mm Hg even in the absence of MR. Moreover, the invasive estimation of PASP is more accurate than using echocardiography.

Furthermore, in patients with severe MR, it is important to diagnose possible latent LV dysfunction. LVEF is load‐dependent. On the other hand, rest GLS < −20% and rest mitral annulus S′ < 10.5 cm/s as well as failure of GLS to improve by >2% and of LVEF to increase by >4% could identify latent LV dysfunction.13 Data are scarce regarding the prognostic role of LA‐CR in evaluating asymptomatic or oligo‐symptomatic patients with severe MR.

2.4.2. Secondary MR

Secondary or “functional” MR constitutes a dynamic condition with complex etiology and a wide range of clinical implications.12 MR could be the result of transient ischemia of the inferolateral myocardial wall or the papillary muscle because of CAD.13 In that case, MR worsens with exertion leading to pulmonary congestion. Subsequently, coronary angiography and revascularization is recommended as it can lead to improvement of the MR degree and LVEF.13

Moreover, MR may result from geometrical distortion of the subvalvular apparatus, due to LV dilation, remodeling, tethering of mitral valve, and reduced closing forces in patients with LV systolic dysfunction. These patients become symptomatic and even manifest with flash pulmonary edema due to worsening of MR severity, attributed to LV dyssynchrony during exercise.13 The dynamic MR due to LV dyssynchrony is a strong negative predictive factor and for these patients, optimal medical treatment and cardiac resynchronization therapy (CRT) are recommended. Importantly, the degree of MR at rest does not correlate with that on exertion and prognosis.12 Therefore, SE plays an important role for the evaluation and risk stratification of patients with secondary MR.

SE is recommended in patients with dyspnea on exertion disproportionate to LV systolic dysfunction or MR severity at rest, acute pulmonary edema without obvious etiology, moderate MR before surgical revascularization, for individual risk stratification and with persistent PH despite MR repair or replacement.2 Parameters that should be evaluated and have prognostic implications are:4, 12

  • Increase in MR severity, estimated with an increase in EROA ≥13 mm2. Estimation of PISA during stress has some limitations and may underestimate the grade of MR. A decrease in MR may suggest viable myocardium (Figure 4).

  • Δ in PASP during stress. An increase in PASP≥60 mm Hg is a strong predictive factor for poor prognosis, independently of PASP and MR severity at rest.

  • LV anterolateral or inferoseptal wall systolic annular tissue Doppler velocity (S′)

  • Mitral annular e′

  • The extent of valve tenting

  • WMA

Figure 4.

Figure 4

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Dobutamine stress echocardiography (DSE) in a patient with ischemic cardiomyopathy. Rest echocardiography reveals (A, B, C), moderately reduced left ventricular ejection fraction (LVEF) 40% with hypokinesia of the basal and mid inferolatelar, inferior, and inferoseptal wall segments and severe secondary mitral regurgitation (MR). Proximal isovelocity surface area (PISA) radius is estimated at 0.72 cm, effective regurgitant orifice area at 16 mm2 and regurgitant volume (RV) at 36 mL/beat. (D), During low‐dose DSE (5 μg/kg/min), motion of the hypokinetic wall segments and LVEF improves, indicating viable myocardium. Importantly, MR severity decreases significantly, with estimated PISA radius 0.63 cm and RV 25 mL/beat. This patient may benefit from revascularization, as it may lead to improvement of MR degree and LVEF

Current ESC/EACTS guidelines recommend exercise SE for risk stratification of patients with dynamic secondary MR.4

2.5. Multivalvular disease

Limited data exist regarding the evaluation of patients with multivalvular disease. Assessment of such patients is challenging and the extension of the early exercise stages is sometimes necessary. Valve anatomy and the pathophysiology of regurgitation are important factors and should be described in detail. In cases that valve regurgitation and stenosis coexist, it is very important to characterize which is the most severe, based on valve morphology and the consequences on atrium as well as on ventricle. On the other hand, evaluation of a patient with more than one valve disease on the same side of the heart (left or right) is very challenging. The interaction between them increases during stress and it is difficult to estimate the severity both at rest and especially during stress. Three‐dimensional (3D) echocardiography provides detailed imaging of the valve anatomy and reveals the pathology of regurgitant or stenotic lesions. However, few data exist regarding the role of 3D transthoracic echocardiography during stress in valve disease evaluation. Bicycle exercise stress is recommended for asymptomatic patients with severe valvulopathies or when symptoms are disproportionate to the severity of valvular disease.2, 14

3. PROSTHETIC VALVES

Exercise or dobutamine SE is helpful in patients with suspected prosthetic valve stenosis or prostheses‐patient mismatch (PPM).2 An increase in transvalvular gradient >20 mm Hg for aortic and >10 mm Hg for mitral valve prostheses or EIPH (PASP>60 mm Hg) indicates severe stenosis or PPM.2, 15 Dobutamine SE is recommended for differentiation between pseudo‐severe and true severe stenosis in patients with low‐flow state.2 If PG remains unchanged during stress, then pseudo‐severe stenosis is diagnosed. Contrarily, true severe stenosis or PPM is recognized by increase in PG. However, in patients with PPM, gradients and estimated orifice area during stress are within normal reference ranges for the prosthetic valve, whereas in true severe stenosis estimated orifice area is lower than normal reference values.2, 15

4. PULMONARY HYPERTENSION

PH is defined as mean pulmonary artery pressure (mean PAP) ≥ 25 mm Hg and can be classified as “post‐capillary” (isolated or combined) or “pre‐capillary”.16 Systolic PAP (PASP) usually increases during exercise in normal individuals.17 Nevertheless, peak exercise PASP>60 mm Hg is abnormal and indicates early stage of PH.18 Some investigators suggest the parameter Δ (mean PAP/workload) ratio as a clinical indicator of PH with prognostic significance.19 Exercise‐induced PH has significant clinical and prognostic value in post‐capillary PH.2, 17

Regarding patients with pulmonary arterial hypertension (PAH), PASP at rest has no prognostic significance.16 The RV‐CR is important for prognosis and disease progression.2 The evaluation of RV size and function (with TAPSE, systolic tricuspid annular tissue Doppler and RV strain) during stress is very important and should always be obtained. Contrary to the aforementioned, an increase in PASP>30 mm Hg during stress indicates RV‐CR and is an independent prognostic factor for improved outcome, compared to patients with modest or no increase in PASP.16

Estimation of PASP during stress has some limitations. Obtaining a high quality signal of the TR jet during exercise is difficult, and a poor quality signal decreases the specificity and sensitivity of the method.19 The infusion of intravenous saline or contrast agent may improve the signal of TR jet. In addition, RA pressure is assumed to be stable ~5 to 10 mm Hg because of difficulties in estimation of the inferior vena cava and its respiratory variations during exercise.19 Other parameters for the evaluation of PASP have not been extensively studied. RVOT acceleration time is an accurate parameter for the estimation of PH, but is rate dependent and its value during stress has not been investigated.

Exercise‐induced PH is recommended as a very accurate parameter for the evaluation of patients with VHD, PAH, high altitude pulmonary edema, and chronic mountain sickness as well as for screening patients at risk for PH (with scleroderma, portal hypertension, sickle cell disease, or HIV infection).2 Supine bicycle or hypoxic SE (hypoxic challenge with the administration of 12% oxygen and 88% nitrogen) is preferred.2

5. HEART FAILURE

SE has an important role in patients with HF.2 Dobutamine SE is the ideal protocol for this group of patients. Moreover, it can be helpful in the differential diagnosis of ischemic and nonischemic cardiomyopathy. Furthermore, SE is a useful tool for the evaluation of LV‐CR in nonischemic HF, both at early stages in patients at risk for HF (hypertensive, diabetics or patients with thalassemia, and chemotherapy), as well as in overt HF.20, 21, 22 The presence of LV‐CR has significant prognostic implications.23 In addition, SE has significant value in monitoring response to treatment with b‐blockers.24 Finally, low‐dose dobutamine SE can predict patients that will be “responders” to CRT.25 The presence of CR or the increase of LVEF by ≥7.5% and the implantation of the LV pacing lead in viable myocardium are good predictors of response to CRT.2, 25 Although exercise SE with longer stages can potentially be used, dobutamine at low or high doses is preferred without the concomitant administration of atropine (if LV‐CR is assessed).2

Parameters obtained during SE are Δ in LVEF, diastolic reserve (estimated with Δ in E/e′ during stress), Δ in PASP, the appearance of dynamic MR and inducible relative WMA.2 Pulmonary congestion with exercise, suggesting elevated pulmonary capillary wedge pressure can be estimated with the appearance of exercise‐induced B‐line in lung ultrasound (ultrasound lung comets‐ULC).2 Stress‐induced B‐lines correlate significantly with NT‐proBNP, E/e′and LVEF and have important diagnostic and prognostic value for patients with acute decompensated HF, both with reduced and with preserved EF. Regarding patients who are candidates for CRT, the viability in the paced area should be additionally evaluated.2, 25

6. HYPERTROPHIC CARDIOMYOPATHY

Exercise SE is an important diagnostic and prognostic tool for the evaluation of patients with hypertrophic cardiomyopathy (HCM). It is recommended for the assessment of functional capacity or response to treatment, exercise‐induced dynamic LVOT obstruction in patients with resting LVOT gradients <50 mm Hg and for sudden cardiac death risk stratification.26, 27

Patients with HCM are classified according to their LVOT pressure gradient (PG) into obstructive (resting LVOT‐PG ≥ 30 mm Hg), nonobstructive (resting LVOT‐PG < 30 mm Hg) and latent obstructive (resting LVOT‐PG < 30 mm Hg, but exercise LVOT‐PG > 30 mm Hg).27 However, a cutoff value for exercise LVOT‐PG has not been established. About 50% of HCM patients, as well as normal individuals, develop LVOT‐PG > 30 mm Hg during exercise. In addition, it seems that patients with exercise LVOT‐PG > 90 mm Hg have a worse prognosis.28

Current guidelines recommend exercise SE in patients with resting LVOT gradient <50 mm Hg despite bedside maneuvers (Valsalva, standing).27 The occurrence of dyspnea, syncope or arrhythmias, a drop in BP, an increase in LVOT‐PG ≥ 50 mm Hg during exercise or at recovery and the degree of dynamic MR are important clinical and negative prognostic factors (Figure S2).26, 27, 28 Furthermore, exercise SE is a useful tool for the evaluation of efficacy of medical treatment with b‐blockers (since they may reduce LVOT obstruction) and septal myectomy.2

PH is often present in patients with HCM and seems to be associated with increased all‐cause mortality.29 The role of EIPH in patients with HCM has not been evaluated. The abrupt increase of PASP and consequently the plateau of Doppler findings during exercise SE indicate worse prognosis and possible candidacy for septal reduction therapy (Figure 5).

Figure 5.

Figure 5

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Stress echocardiography with semi‐tilted bicycle in an asymptomatic patient with hypertrophic obstructive cardiomyopathy. At rest (A, B), peak left ventricular outflow tract pressure gradient is estimated at 55 mm Hg and systolic pulmonary artery pressure (PASP) at 35 mm Hg. At peak stress (C), the patient becomes symptomatic and PASP significantly increases at 79 mm Hg

In addition, evaluation for inducible myocardial ischemia is of clinical and prognostic importance. Stress testing for diagnosis of CAD in patients with HCM has a high negative predictive value but low specificity, since ischemia can occur in the absence of significant epicardial stenosis (hypertrophy, microvascular disease, and LVOT obstruction or myocardial bridging) and therefore, coronary angiography is indicated.26 The assessment of coronary flow reserve with SE or with stress cardiac magnetic resonance (CMR) seems to have no prognostic value for patients with HCM.

Exercise SE with semi‐tilted bicycle is recommended but, if no LVOT obstruction is revealed, then exercise in an upright position should be considered, because standing decreases preload. For the same reason, parameters should also be obtained at the beginning of the recovery period.2 Patients already on b‐blockers are advised to continue treatment for the interpretation of SE.2 Dobutamine SE is not recommended, because it is not physiological and may induce LVOT obstruction even in normal individuals.26 The only indication is during septal myectomy, for evaluation of the procedure's efficacy with estimation of LVOT‐PG and MR.2 The parameters that should be evaluated are BP response, LVOT‐PG, LV systolic function (Δ in LVEF), LV diastolic function (Δ in E/e' ratio) and the occurrence of dynamic MR.

7. ATHLETES' HEART

Exercise SE is recommended in symptomatic athletes for the evaluation of intraventricular pressure gradients, PASP, MR, and pulmonary congestion with ULC.2 However, ULC seem to appear even in healthy athletes after strenuous exercise.2 Furthermore, SE is a useful tool for the evaluation of some athletes with “low” resting LVEF. As expected, a normal increase in LVEF during exercise is indicative of normal systolic function.30

Exercise SE is very important for the differentiation between HCM and athletes' heart.30 Left ventricular end‐diastolic volume is normal compared to HCM, where it is decreased. During exercise, patients with HCM may have abnormal BP response and global or regional systolic dysfunction. Diastolic dysfunction with increase in E/e′ ratio and LVOT obstruction occurs in HCM patients, but not in athletes.

8. DIASTOLIC DYSFUNCTION

Patients with dyspnea and fatigue on exertion and preserved LVEF should be evaluated for diastolic dysfunction. E/e′ ratio and PASP at rest and during exertion seem to correlate with LV end‐diastolic filling pressure (LVEDP) and have a strong predictive value.31 HF with preserved ejection fraction (HF‐pEF) is confirmed if E/e′ratio is >15 and excluded if E/e′is <8.31 Exercise SE (diastolic SE) is recommended for symptomatic patients or patients at risk for HF‐pEF (diabetics, hypertensive, elderly, or obese) with preserved EF, grade I diastolic dysfunction and E/e′ratio between 8 and 15 (“gray zone”) at rest.31

Semi‐tilted bicycle is preferred, but treadmill exercise SE could be an alternative. For patients unable to exercise, the passive leg raise results in preload augmentation and could be applied instead.2, 32 Dobutamine SE should not be the preferred method.2 Images must be obtained at rest, peak exercise, and early stages of recovery. Parameters that are usually measured are E/e′, e′ velocity, PASP, and cardiac output or SV.2 E and A values should be obtained at heart rate 100 to110 bpm, when they are not fused.2

Diagnosis of HF‐pEF is confirmed with the presence of: (a) exercise E/e′average > 14 or septal >15, (b) exercise peak TR velocity > 2.8 m/s, and (c) resting septal e′ velocity < 7 cm/seconds or lateral e′ < 10 cm/seconds.2, 32 However, the sensitivity and specificity of E/e′ratio as a diagnostic marker for HF‐pEF and elevated LVEDP is not well established and cannot differentiate diastolic dysfunction from other causes of elevated LVEDP during stress (CAD, VHD, or cardiomyopathies).33, 34 In addition, most studies have excluded patients with AF, although AF occurrence during dobutamine SE seems to have a prognostic implication for the incidence of HF or CAD in the future.35 More diagnostic criteria are needed for the evaluation of HF‐pEF in those patients.

9. CONGENITAL HEART DISEASE

Data regarding the value of SE in patients with CHD are scarce. Exercise and dobutamine SE seem to be of significant importance for detection of CAD and assessment of RV or LV‐CR in adult patients with CHD.2, 36 Furthermore, SE may be a useful tool for evaluation of post‐operative pulmonary regurgitation or after percutaneous pulmonary valve implantation in young patients with repaired Tetralogy of Fallot.37 Exercise SE is the preferred method and PASP, TAPSE, RV fractional area change or RV diastolic function with TDI and E/e′ during stress are very useful parameters for the evaluation of RV function and CR.38 In addition, Δ in LVEF, SV with VTI in LVOT during dobutamine SE for patients late after Fontan operation offers important information for LV‐CR. Finally, subaortic pressure gradient for patients with subaortic membrane or pressure gradient at descending aorta for patients with aortic coarctation should be assessed at rest, low workload and peak exercise.2, 36, 37

10. HEART TRANSPLANTATION

The role of SE after heart transplantation has not been well established. These patients have decreased chronotropic response, due to denervated heart, and increased pulmonary vascular resistance. Dobutamine SE is the preferred method for those patients. However, exercise SE with semi‐tilted bicycle, when combining TDI and longitudinal strain parameters with maximum achieved heart rate, seems to offer important clinical and prognostic information for the evaluation of LV and RV function in children after heart transplantation.39 Cardiac allograft vasculopathy (CAV) is characterized from diffuse intimal hyperplasia and smooth muscle cell proliferation of coronary arteries, and rarely causes focal luminal stenosis. Subsequently, coronary angiography alone is not very accurate for diagnosis and is often combined with intravascular ultrasound (IVUS) and fractional flow reserve. Many studies have highlighted the role of dobutamine SE in the early and noninvasive diagnosis of CAV. It seems that coronary flow reserve is impaired early at CAV, since the disease affects microcirculation first. In addition, sensitivity and specificity of IVUS increases significantly when combined with dobutamine SE. Recent guidelines recommend SE for the detection of CAV in heart transplant recipients unable to undergo invasive evaluation.40 On the other side, SE is of limited value in the setting of acute rejection. More studies are needed to confirm the role of SE in patients with heart transplantation.

11. COMPARISON OF STRESS ECHO WITH OTHER IMAGING MODALITIES

Single‐photon emission computerized tomography and positron emission tomography scan, computed tomography and CMR in combination with exercise or pharmacological stress have a great diagnostic and prognostic value in the evaluation of myocardial perfusion and metabolism. Nevertheless, data regarding the role of those methods in nonischemic heart disease are scarce. CMR is the best imaging method for the evaluation of CHD, RV function, PH, and HCM. However, stress‐CMR in nonischemic heart disease does not have clinical application yet, because of many limitations. First of all, this examination is performed only with pharmacological stress and not with exercise. Therefore, we obtain much less clinical information for the patient than with SE. In addition, this is a time‐consuming and very expensive exam, whereas the patient feels very uncomfortable and anxious. Finally, the increase in breath and heart rate or the occurrence of AF or premature ventricular complexes during stress may cause many artifacts and decrease the accuracy of this method significantly, since patient's cooperation and breath‐holding is essential. Subsequently, SE remains the imaging modality of choice for the evaluation of patients with nonischemic heart disease.

12. CONCLUSIONS

SE seems to be of great importance for the evaluation of patients with many pathological conditions beyond CAD. It is an established method for the evaluation of symptomatic and asymptomatic patients with VHD and cardiomyopathies, and provides important information regarding prognosis and management of patients with CHD, PAH, or diastolic dysfunction. Data from future and ongoing prospective clinical studies are needed to establish the use of SE in all these conditions.

CONFLICTS OF INTEREST

The authors declare no potential conflicts of interest.

Supporting information

Figure S1 Comparison of hemodynamic effects of the different stress echocardiography protocols. BP, blood pressure; HR, heart rate; INO, inotropic response.

Figure S2: Stress echocardiography with semi‐tilted bicycle in a patient with syncope due to hypertrophic cardiomyopathy (HCM) and latent left ventricular outflow tract (LVOT) obstruction. At rest (A), peak LVOT pressure gradient is estimated at 22 mm Hg. During stress (B) the patient manifests dynamic LVOT obstruction with peak LVOT pressure gradient at 66 mm Hg.

Click here for additional data file. (259.9KB, pdf)

Aggeli C, Polytarchou K, Varvarousis D, Kastellanos S, Tousoulis D. Stress ECHO beyond coronary artery disease. Is it the holy grail of cardiovascular imaging? Clin Cardiol. 2018;41:1600–1610. 10.1002/clc.23094

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1 Comparison of hemodynamic effects of the different stress echocardiography protocols. BP, blood pressure; HR, heart rate; INO, inotropic response.

Figure S2: Stress echocardiography with semi‐tilted bicycle in a patient with syncope due to hypertrophic cardiomyopathy (HCM) and latent left ventricular outflow tract (LVOT) obstruction. At rest (A), peak LVOT pressure gradient is estimated at 22 mm Hg. During stress (B) the patient manifests dynamic LVOT obstruction with peak LVOT pressure gradient at 66 mm Hg.

Click here for additional data file. (259.9KB, pdf)

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