Stress Echocardiogram in Asymptomatic Severe Aortic Stenosis.

Aortic stenosis (AS) is one of the most common adult valve diseases. Therefore, current guidelines recommend prompt aortic valve intervention once symptoms occur. However, AS is predominantly a disease of the elderly, and these people may be underreporting their symptoms, have other comorbidities, or have a low level of exertion at the baseline or they might make a subconscious adjustment of their activities. Hence, stress testing can be a vital and objective tool to uncover their symptoms and prognosticate. Copyright:

INTRODUCTION

In developed countries, aortic stenosis (AS) is the most common type of adult valve disease that requires treatment. Valvular AS is progressive, characterized by worsening valve obstruction; end-stage severe AS results in decreased cardiac output, heart failure (HF), and premature death.[123]

AS is predominantly a disease of the elderly, with prevalence increasing from 0.2% among adults between 50 and 59 years of age to nearly 10% in octogenarians, with an overall prevalence of 2.8% among those >75 years of age.[456]

Once symptomatic, the prognosis of AS is poor unless aortic valve replacement (AVR) is performed 4–6. Therefore, current guidelines recommend AVR for patients with severe AS who are symptomatic (Class I indication).[789]

Around 50% of patients with severe AS report no symptoms at initial diagnosis in clinical practice. Irreversible myocardial damage or sudden cardiac death can occur if symptoms are overlooked and treatment is deferred.[10]

The increase in stenosis severity is gradual and so patients may unconsciously adjust their activity level to avoid symptoms. They are not recognizing that these symptoms are of concern or they may attribute their symptoms to some other cause, such as age.[11]

Stress testing with adjunctive imaging may further unmask the symptoms and other unfavorable characteristics that are not apparent at rest; recent data imply that several of these indices might be helpful in risk stratification.[121314]

DEFINITION AND DIAGNOSTIC EVALUATION

AS is defined by the aortic valve area (AVA) and blood flow velocity across the valve as assessed by transthoracic echocardiography. For patients with normal left ventricular ejection fraction (LVEF), severe AS is defined as (1) AV area <1.0 cm2 or AV area index <0.6 cm2/m2, (2) aortic jet peak velocity more than 4.0 m/s, or (3) transvalvular mean pressure gradient more than 40 mmHg.

AS progression can be unpredictable, and therefore, it is important to follow patients closely and be vigilant for the onset of symptoms. Similarly, due to technical challenges, variability, and discordances in the echocardiographic acquisition of currently recommended severity grading criteria, symptoms might develop before classical echocardiographic standards for severe AS are met. Last, some entities of low-flow state (SVI <35 mL/m2 and mean flow rate <200 mL/s) presenting with an AVA <1.0 cm2 but nonsevere gradient (low flow/low gradient with reduced LVEF or paradoxical low flow/low gradient with preserved LVEF) may also represent a challenging situation and area of discrepancy in AS severity assessment.[15]

ASYMPTOMATIC SEVERE AORTIC STENOSIS

Some adults with severe AS remain asymptomatic for several years, even in the setting of vigorous physical activity. They have stage C AS. The reasons why some patients tolerate abnormal valve hemodynamics better than other patients are not clearly understood. However, most of these patients develop symptoms within a few years, with a rate of symptom onset of 40% per year. The likelihood of symptom onset increases as aortic velocity increases.

Symptom onset occurs within 1 year in 36% of those with an aortic velocity >5 m/s and in 66% of those with a velocity >5.5 m/s.

The risk of sudden death is low (<1% per year) in adults with severe asymptomatic AS with a preserved LVEF. However, patients need to understand the importance of promptly reporting symptom onset. When severe AS is present, any added hemodynamic burden may result in hemodynamic compromise. Thus, any intercurrent illness, fever, gastrointestinal bleeding, pregnancy, or noncardiac surgery may precipitate symptom onset. Clinical deterioration also can occur with new-onset atrial fibrillation.

STRESS TESTING IN AORTIC STENOSIS

In severe AS, exercise testing is helpful in “asymptomatic” patients to evaluate functional capacity and confirm asymptomatic status. Almost a third of the patients who are asymptomatic severe actually have symptoms during stress testing. Patients with symptoms induced by exercise testing (exercise-induced angina, early exercise-induced dyspnea, syncope, or presyncope) should be considered to have symptomatic AS.

A decrease in systolic blood pressure ≥10 mmHg during peak exercise or a lower exercise tolerance than expected for age and sex suggests that symptom onset is imminent. Electrocardiographic ST-segment changes are not specific when AS is present, with significant ST depression seen in 80% of adults with AS, regardless of whether the coronary disease is present.

Although exercise testing is relatively safe in asymptomatic patients, symptomatic patients with severe AS should not undergo exercise testing due to the high risk of complications, including syncope, ventricular tachycardia, and death.

Stress testing can be performed either by exercise or with pharmacological means. As exercise stress testing (EST) is more physiological, it is considered to have more robust support in the medical literature; it is, therefore, the optimal method for risk stratifying patients with AS who can exercise.[16]

It is essential to rule out the following contraindications before performing the test: (1) an established indication for AVR, (2) uncontrolled hypertension, (3) symptomatic or hemodynamically significant arrhythmias, and (4) inability to perform the test such as orthopedic limitations or global disabilities.[317]

STANDARD ECHOCARDIOGRAPHIC MEASURES OF AORTIC STENOSIS SEVERITY

In the setting of a normal transaortic valvular flow rate or a high-gradient state, the key measures of AS severity on echocardiography are the peak aortic velocity and mean transaortic gradient. Aortic velocity is measured using continuous-wave Doppler ultrasound examining multiple acoustic windows.

The mean gradient is calculated by averaging instantaneous gradients over the systolic ejection period using the modified Bernoulli equation, which states that the pressure gradient equals four times the velocity squared. The valve area is calculated using the continuity equation. Critical measures of severe high-gradient AS include a peak aortic valve velocity ≥4 m/s and a mean aortic valve gradient ≥40 mmHg. The valve area typically is ≤1 cm2 but may be larger with mixed stenosis and regurgitation or in patients with large body habitus.

STRESS ECHOCARDIOGRAPHY IN AORTIC STENOSIS

Stress echocardiographic protocols focus on the valve or left ventricle (LV)-related parameters and hemodynamics. Stress echocardiography is more physiological, so it is recommended in patients with asymptomatic AS who can exercise, whereas dobutamine stress echocardiography is the test of choice for patients with low-gradient, reduced ejection fraction AS that is deemed severe based on AVA calculation.

Echocardiography after exercise can be performed after traditional treadmill or bicycle ergometer exercise, but bicycle exercise is the recommended exercise technique when stress echocardiography is performed. With supine or semi-supine bicycle stress, echocardiography, imaging, and Doppler assessment can be performed continuously throughout the testing period.[16]

In patients with moderate or severe AS, a significant exercise-driven rise in the mean gradient of pressure can be accompanied by an elevated risk of unfavorable events (that may include development of symptoms, cardiac death, or symptom-driven AV replacement), with an increase >18 mmHg or >20 mmHg considered pathological.[1819]

Changes in a pressure gradient that is exercise induced have significant value over the treadmill exercise test and rest echocardiographic measurements. From a pathophysiological perspective, the increase in pressure gradient during exercise can occur because the AS is severe at baseline, which results in a more significant increase in the pressure gradient for a known rate of flow during stress testing or due to noncompliance and rigidity of aortic valve that can prevent an increase in orifice area during stress testing. As there is a close relationship between the flow rate and the pressure gradient, exercise-related changes in gradient better are interpreted in the view of the stroke volume measurement. If the stroke volume increases markedly during exercise, the gradient can increase considerably even in a compliant valve.[202122]

As changes in stroke volume are prognostic in AS, so measurement of its changes with exercise is important. Lack of increase of stroke volume during exercise is considered pathological and can be associated with increased events (with death and AVR is considered an event).[2324252627]

Two novel exercise echocardiographic indices are emerging beyond pressure gradient and left ventricular functional parameters. First, the development of pulmonary hypertension (systolic pulmonary arterial pressure >60 mmHg) at peak exercise has been associated with a two-fold increased adjusted risk of cardiac events (cardiovascular mortality or requirement for AV replacement secondary to symptoms or depressed LV function). Whereas pulmonary hypertension at baseline is a strong predictor of worse outcomes even if the patient undergoes AVR, and is often associated with symptoms, pulmonary hypertension that develops only during exercise represents an earlier disease stage. Intervention before the onset of chronic pulmonary hypertension may improve prognosis. Second, impaired global longitudinal strain (using various cutoffs values and a linear metric) has been observed in patients with severe AS and is believed to reflect subendocardial cardiomyocyte dysfunction secondary to concentric remodeling and myocardial fibrosis.[28]

The global longitudinal strain has been assessed recently as a helpful measure to evaluate exercise-induced changes and can be assessed by speckle-tracking or tissue Doppler imaging and may predict a reduction in the contractile reserve, but these trials did not examine the relationship between exercise-induced changes in global longitudinal strain and clinical events 26. Hence, the association between changes in global longitudinal strain during exercise and clinical outcomes needs to be confirmed.[293031]

In summary, among asymptomatic AS patients, exercise echocardiography is a diagnostic modality that can continuously assess key parameters related to valve anatomy and physiology during the exercise. It appears to offer incremental value over the traditional exercise test and baseline echocardiography, but its importance in asymptomatic AS needs to be proven in more robust studies.

The European Society of Cardiology/European Association for Cardio-Thoracic Surgery but not the American College of Cardiology/American Heart Association guidelines recommend that for asymptomatic severe AS patients with preserved LVEF and high gradient, AVR could be considered for patients with >20 mmHg increase in mean gradient during exercise (Class IIb) 1.[123]

STRESS TESTING ROLE IN CLINICAL DECISION-MAKING

The decision to refer a patient with asymptomatic severe AS to surgery is critical and needs good justification. Stress testing is helpful to recognize symptomatic patients who are thought to be asymptomatic. Asymptomatic patients with severe AS and reduced or subnormal LV systolic function should be referred for surgery (Class I).[7]

Figure 1 illustrates current guidelines regarding stress echocardiogram. Suppose the patients with preserved LVEF develop spontaneous valve-related symptoms during follow-up or EST. In that case, both the European Society of Cardiology/European Association for Cardio-Thoracic Surgery and the American College of Cardiology/American Heart Association guidelines recommend referral for AVR (Class I).[7] If there is a pathological response to stress testing, such as no increase in blood pressure or malignant happened during the stress testing, then it is recommended to proceed for AVR (Class IIa).

Figure 1

Current guidelines regarding stress echocardiogram in asymptomatic severe aortic stenosis

Exercise testing should be considered in any asymptomatic patient with severe AS and preserved LV systolic function, especially if there is a concern regarding the accuracy of the history or there is a need to assess the safety of occupational work or daily activities. If the patient cannot perform an exercise test, then other stratification methods, such as baseline and follow-up biomarkers (e.g., B-type natriuretic peptide), could be helpful. If the exercise test is normal (the patient does not report symptoms or fulfills the other criteria for an abnormal test), a short-term prognosis is reasonable, and clinical/ echocardiographic follow-up can continue as per current guidelines.[789] Recognition and reporting of symptoms between visits are essential to reduce the risk of sudden cardiac death (which is low among this population) and disease progression, irreversible myocardial damage, and the development of other significant complications, including atrial fibrillation and HF hospitalization.

Current guidelines recommend repeat echocardiography every 6–12 months for severe AS and every 12–24 months for moderate AS but are silent about whether an exercise test should be repeated at each follow-up. Given the variability in symptoms reporting and the assiduousness of clinical follow-up, repeat stress testing could be seen as reasonable.

Exercise echocardiography can add significant additional prognostic data. High-risk features such as an exercise-induced increase in mean pressure gradient of ≥ 20 mmHg may motivate closer follow-up.[30] In fact, given the currently low procedural mortality and morbidity rates for isolated surgical AVR and transcatheter AVR, earlier intervention may be favorable for at least a subset of these patients. As discussed earlier, the European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines acknowledge that AVR can be considered for patients whose mean gradient increases by ≥20 mmHg during exercise (Class IIb).

Recent trials showed the potential benefit of elective AVR in asymptomatic patients with severe AS compared to watchful waiting, especially if the AV area is <0.75 cm2 or mean gradient more than 50 mmHg.[10] Finally, as there are limitations and challenges of the present anatomic and valve-focused grading system (severe, moderate, and mild) and the unfavorable prognosis associated with a positive stress test in patients with moderate or severe AS, a multimodal stratification scheme incorporating both anatomic (echocardiogram) grading criteria and physiological (stress test) assessment of AS might represent a more appropriate investigational strategy when facing patients with severe or even moderate asymptomatic AS.[32] Advantages of such a novel and more aggressive strategy in which early screening of potential AVR candidates is performed using a multimodal approach include balancing intrinsic limitations associated with each modality and identifying early AS-related repercussions not captured by more conventional anatomic criteria. Further prospective studies are needed to validate such an approach.

CONCLUSIONS

Around half of the patients with severe AS do not report their symptoms. Therefore, exercise testing is helpful to identify whether patients are truly asymptomatic. Traditional treadmill exercise testing or bicycle ergometer is safe. It is well established that patients with AS and an abnormal exercise test have a worse prognosis unless AVR is performed. Exercise echocardiography can complement the traditional symptom-based exercise test with detailed valve structure and function information, but more experience with these techniques is necessary.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.