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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 71-77

Stress echocardiography in aortic stenosis


Department of Cardiology, Jupiter Hospital, Thane, Maharashtra, India

Date of Web Publication29-Aug-2019

Correspondence Address:
Nitin Burkule
Jupiter Hospital, E. Ex. Highway, Thane - 400 606, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiae.jiae_41_19

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  Abstract 

In apparently asymptomatic severe aortic stenosis (AS) group, stress echocardiography objectively identifies symptomatic, high-risk AS patients requiring early aortic valve replacement (AVR). The low-flow, low-gradient AS is well-characterized clinical entity with distinct diagnostic, management, and clinical outcome challenges. A comprehensive two-dimensional transthoracic echocardiography (2D echo) and Doppler and low-dose dobutamine stress echocardiography are of paramount importance for accurate diagnosis and timely decision of AVR. However, clinicians and imaging experts should be aware of the pitfalls and inaccuracies inherent in 2D echo/Doppler measurements and the effects of pathophysiological factors which impact the stroke volume and transvalvular gradient measurements. In appropriate clinical situations, clinicians should take additional help of cardiac computational tomography, cardiac magnetic resonance imaging, and biomarkers.

Keywords: Low-flow, low-gradient aortic stenosis, low-gradient aortic stenosis, paradoxical low-flow, pseudo-severe aortic stenosis, transcatheter aortic valve replacement


How to cite this article:
Burkule N. Stress echocardiography in aortic stenosis. J Indian Acad Echocardiogr Cardiovasc Imaging 2019;3:71-7

How to cite this URL:
Burkule N. Stress echocardiography in aortic stenosis. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2019 [cited 2019 Nov 17];3:71-7. Available from: http://www.jiaecho.org/text.asp?2019/3/2/71/265756


  Introduction Top


With increasing aging population and inadequately treated hypertension (HT) in the community, cardiologists are more frequently diagnosing elderly patients of degenerative calcific aortic stenosis (AS) with multiple comorbidities. The common comorbidities are HT, diabetes mellitus, chronic obstructive pulmonary disease, obesity, obstructive sleep apnea, anemia, chronic kidney disease, age-related frailty or deconditioning, atrial fibrillation, mitral degenerative disease, coronary disease, and hypothyroidism.[1] This makes symptom evaluation and correlation of symptoms to severity AS very difficult.[2]

The evaluation of these patients needs a careful and thorough clinical, B-type natriuretic peptide (BNP) biomarkers, two-dimensional transthoracic echocardiography (2D echo)/Doppler assessment, and stress imaging. These patients will either present with preserved or reduced left ventricular (LV) ejection fraction (EF) and may or may not be symptomatic.


  Types of Aortic Stenosis With Low or Normal Ejection Fraction Top


The aortic transvalvular gradient depends not only on aortic valve area (AVA) but also on transvalvular flow rate (TVFLR) and stroke volume (SV) or indexed SV (SVi) to body surface area (BSA). The patients with severe AS can be classified into the following four groups depending on normal flow (NF, SVi >35 ml/m 2) or low flow (LF, SVi <35 ml/m 2) and high gradient (HG, mean gradient >40 mmHg) or low gradient (LG, mean gradient <40 mmHg)[3]:

  1. NF/LG
  2. NF/HG
  3. LF/HG
  4. LF/LG.


The above groups from the first (NF/LG) to the fourth (LF/LG) probably describe progressively more advanced disease state implying more LV myocardial fibrosis, more adverse cardiac event rates, and higher mortality with surgical aortic valve replacement (AVR). This also correlates with progressively higher BNP levels in the successive groups.[3] However, these are not chronological stages in the natural history of AS for an individual patient.[2]


  Rationale of Stress Echocardiography in Aortic Stenosis Top


High-gradient severe aortic stenosis

The therapeutic decision is relatively straightforward in the patients with severe AS and HG either in the NF/HG or LF/HG group, with or without low EF. The patients with low EF irrespective of symptoms are referred for AVR. However, patients with normal EF are referred for AVR only if symptomatic or have very high AS gradient (peak aortic velocity >5 m/s, mean gradient >60 mmHg).[4]

The natural history of asymptomatic AS is not benign. In a series of 622 patients with asymptomatic severe AS, Pellikka et al.[5] found probability of 5-year survival <60%. In another study of 239 patients with asymptomatic severe AS, Pai et al.[6] noted 3-year overall survival rate of 38%. The contemporary study of natural history of 103 patients of asymptomatic severe AS by Zilberszac et al.[7] showed the risk of death or symptoms and AVR to be as high as 27% at 1 year, 57% at 2 years, 77% at 3 years, and 84% at 4 years. The symptom onset is often abrupt and severe, and the primary cause of death is not sudden cardiac death (SCD) but acute congestive heart failure (CHF). The rapid clinical deterioration is associated with increased operative mortality and poorer long-term postoperative survival.[7]

Patients with AS are older and have extensive comorbidities. The physical mobility is impaired in approximately one-third of these patients.[7] The detection of early symptoms in elderly patients, attributable to severe AS, is difficult during clinical follow-up. One-third of patients, who claim to be asymptomatic, develop symptoms on treadmill or bicycle exercise. No SCD is reported in patients with severe AS with normal exercise stress test.[8]

Low-gradient severe aortic stenosis

The symptomatic LG severe AS group is more challenging for decision regarding AVR. The entity of NF/LG AS is supposed to be misclassification of moderate AS due to errors in echo/Doppler measurements and inherent discrepancies of gradient and AVA (between 0.8 and 1 cm 2) in the severity grading of guidelines.[9] The entity LF/LG severe AS is further classified into two groups: LF/LG group with preserved EF (paradoxical LF, LG severe AS) and LF/LG group with low EF (classical LF, LG severe AS).

Classical low-flow, low-gradient severe aortic stenosis

The low-dose dobutamine stress echocardiography (LDDSE) challenge in classical LF, LG severe AS is aimed at augmenting the SV and/or TVFLR. The transvalvular gradient and true AVA are measured at optimized flow conditions, i.e., SV >35 ml/m 2 or rise in SV >20% from baseline and/or TVFLR >200–250 ml/s. The dobutamine may augment the SV >20% of baseline (contractile reserve present, CR+ve) or may fail to augment SV (contractile reserve absent, CR−ve). In the presence of CR+ve at optimized flow conditions, the AVA may remain <1 cm 2 (true-severe AS) or may increase to >1.1–1.2 cm 2 (pseudo-severe AS with concomitant cardiomyopathy). The perioperative mortality of surgical AVR is higher in CR−ve patient group than the CR + ve patient group.[10]

Paradoxical low-flow, low-gradient severe aortic stenosis

Compared to classical LF/LG AS (low EF), the paradoxical LF/LG AS (preserved EF) group shows similar higher surgical AVR perioperative mortality (6.3%) but better midterm post-AVR survival.[11] The PARTNER trials showed, in prospective and randomized fashion, a better survival of paradoxical LF/LG patients by transarterial AVR (TAVR) compared to either medical management (in inoperable patients) or surgical AVR (in high-risk patients).[12]

However, SEAS study and Tribouilloy et al.[2] report no difference in clinical outcome of paradoxical LF/LG group compared to moderate AS group or NF/LG group and no significant benefit with AVR in all three groups compared to conservative management.[1],[2] Some studies have indicated that LF/LG patients have larger AVAs on magnetic resonance imaging (MRI), lesser valve calcification, lesser weight of explanted aortic valve, and lesser Left ventricular hypertrophy (LVH) and myocardial fibrosis compared to HG AS subgroup.[2]

There are many reasons to explain this apparent conflict in the literature. It is evident that the LF/LG group with preserved EF is a heterogeneous group prone to get mixed up with low-risk patients from NF/LG group and moderate AS group due to various factors [12],[13],[14] as follows and should be carefully ruled out before diagnosing paradoxical LF LG severe AS:

  • Measurement errors: The SV calculation is a critical step. Falsely low SV will misclassify low-risk moderate AS or NF/LG patient as LF/LG severe AS. Therefore, when encountered with discrepant values, it is crucial to verify the SV by other methods such as 3D/2D LV volume calculation or cardiac MRI. The aortic flow continuous-wave (CW) Doppler interrogation should be done through all possible windows. A frequently nonaligned CW Doppler spectrum will give lower mean gradient and can misclassify HG severe AS to moderate AS or NF/LG or LF/LG group
  • Indexing to BSA: If AVA is indexed to BSA (severe AS <0.6 cm 2/m 2), lesser number of women with small stature will get classified as severe AS. However, at the other extremes, a greater number of obese patients on routine indexing of AVA to large BSA will get classified as severe AS. Paradoxically, obesity has a favorable effect on AS or heart failure outcome
  • Discrepancy in guideline: Severe AS is defined as AVA <1 cm 2 and mean gradient >40 mmHg. However, at normal TVFLR (>250 ml/s) and heart rate (HR), the Gorlin's equation yields 1 cm 2 AVA for a mean gradient of 30–35 mmHg. This may explain the NF/LG severe AS group which may be at the benign end of the spectrum of AS disease process
  • High systemic vascular resistance (SVR): The LF/LG patients typically have high SVR and high valvuloarterial impedance (high Zva >4.5) and restrictive LV filling which are conspicuously absent in NF/LG group. The high SVR and high systolic blood pressure (BP) may reduce SV. The measurement of SVi after clinical control of BP, for adequate duration, by vasodilators may reclassify them into low-risk NF/LG group
  • Pseudo AS: The paradoxical LF/LG AS group (with preserved EF) may hide a subset of pseudo AS patients (moderate AS with inadequate opening of valve due to LF rates and low SV) such as classical LF/LG AS group (with low EF). It is estimated that about 30% of LF/LG patients are pseudo AS.


The LDDSE challenge in paradoxical LF LG AS poses a unique problem. These elderly patients are hypertensive, have severe concentric LV hypertrophy, reduced LV end diastolic and end systolic volumes, and reduced LV longitudinal contractile function.[13] On dobutamine challenge, they fail to increase SV or reach TVFLR >250 ml/s. The Quebec group has proposed calculation of hypothetical projected AVA at flow rate of 250 ml/s as follows:[14]



Qrest = TVFLR at rest and Qpeak = TVFLR at peak dose of dobutamine when the test was terminated. AVAproj = AVA projected at TVFLR of 250 ml/s, AVArest = AVA at rest, and AVApeak = AVA at peak dose of dobutamine when the test was terminated. In a study by Annabi et al.,[15] the projected AVA on LDDSE correctly classified the largest percentage of patients to true- or pseudo-severe AS compared to conventional parameters, as confirmed intraoperatively or by computed tomography (CT).

The patients with paradoxical LF/LG AS have high SVR which increases the valvuloarterial impedance or afterload leading to reduction in SV. In an invasive hemodynamic measurement study,[16] the Mayo group evaluated the use of sodium nitroprusside challenge to reduce the afterload and augment the invasively measured SVi and aortic mean gradient to differentiate pseudo- and true-severe AS in paradoxical LF LG AS.[16] The AVA calculated by Gorlin's formula increased to >1 cm 2 in 25% of patients, regardless of baseline SV and SVR, leading to reclassification from severe to moderate AS.


  Performance of Exercise Stress Echocardiography in Asymptomatic Severe Aortic Stenosis Top


The graded treadmill or upright bicycle test-exercise test protocol, tailored to the ambulatory status of the patient, is recommended to reach at least 80% of age-predicted target HR (THR). If the patient develops symptoms, hypotension, or ventricular arrhythmias, or achieves 80% THR, the exercise test is terminated promptly. Abnormal response is characterized by >1 of the following events during exercise:[8]

  • Angina, dyspnea, dizziness, and syncope
  • >2-mm ST-segment depression from baseline
  • Fall in systolic BP >20 mmHg or below baseline value
  • Complex ventricular arrhythmias (nonsustained ventricular tachycardia, >3 ventricular premature beats in a row).


The echo/Doppler imaging and pulmonary gas exchange measurements can be coupled with bicycle stress testing to gather additional hemodynamic data. The exercise-induced increase in mean gradient >20 mmHg is associated with 3.8-fold increase in risk of cardiac event on follow-up.[17] The exercise-induced increase in pulmonary artery systolic pressure (PASP) >60 mmHg is independently associated with a 2-fold increase in risk of cardiac event at 3-year follow-up.[8]

The positive stress echocardiography results in asymptomatic AS are characterized as follows:[8]

  • Increase E/e' ratio >14
  • AS mean gradient >20 mmHg
  • Pulmonary artery systolic pressure (PASP) >60 mmHg
  • Worsening in LV Regional wall motion abnormality (RWMA)
  • Reduced LV contractile reserve (EF fall/increase < 5%)
  • LV global longitudinal strain (GLS) fall or increase <–1.4%
  • S'-wave velocity increase <5 cm/s
  • Peak VO2 <84% age- and sex-predicted values.


The role of stress echocardiography in AS for predicting outcome was challenged by the study of Goublaire et al.[18] In the exercise testing of 148 patients with asymptomatic AS, one-fourth had real symptoms, fall in BP, and ST-segment depression and one-third had exercise-induced increase in mean gradient >20 mmHg and a PASP >60 mm Hg. However, only resting mean gradient >40 mmHg and not the exercise-induced increase in mean gradient or PASP predicted event-free survival over next 2 years.

The resting echo/Doppler parameters which can detect the severity of LV myocardial hypertrophy, fibrosis, and subclinical dysfunction may be important for decision of early AVR in asymptomatic AS. These parameters may be reported in stress echo report as follows:[8],[19],[20]

  • LVEF by 3D or Simpson's method.
  • LV mass by 3D or M-mode.
  • 2D LV GLS
  • 3D LV GLS and global radial strain
  • LV midwall shortening
  • E/e' >15
  • E/early diastolic strain rate >1.04.



  Performance of Low-Dose Dobutamine Stress Echocardiography in Low-Flow/low-Gradient Severe Aortic Stenosis Top


SVi (SV/BSA) is influenced by the LV contractility, geometry, and global afterload, and TVFLR (SV/systolic ejection time [ET]) is influenced by aortic valve resistance and LV contractility. SVi <35 ml/m2, not LVEF, is an independent predictor of 2-year mortality after AVR.[21] The low TVFLR is independently associated with higher CV mortality and all-cause mortality.[22] Low TVFLR is associated with older age, female sex, smaller body size, lower LV mass, low SVi, high SVR, and in inconsistently graded severe AS.[22] Low TVFLR predicts higher mortality in paradoxical LF LG AS.[23] Therefore, careful measurement of LV outflow track (LVOT) diameter and velocity time integral (VTI) of LVOT pulse wave (PW) spectral Doppler and systolic ET is of paramount importance and should be performed as per the American Society of Echocardiography guidelines [9] [Figure 1].
Figure 1: The measurements of left ventricular outflow track cross-sectional area, left ventricular outflow track velocity time integral, aortic flow velocity time integral, systolic ejection time, and acceleration time

Click here to view


At rest, patient's BSA, BP, HR, and rhythm should be recorded. The LVOT diameter in mid-systole in parasternal long-axis zoomed view should be measured, and the same value can be utilized in subsequent stages of LDDSE for calculation of SV. The dobutamine infusion is started at 2.5 μg/kg/min, and the dose is increased every 3 min by 2.5 or 5 μg/kg/min to a maximum of 20 μg/kg/min.[9] The HR should not increase >20 beats/min over baseline as it may shorten the systolic ET and cause fall in SV. However, the TVFLR continues to rise with modest increase in HR from baseline, despite falling or static SV. The BP and Electrocardiogram (ECG) should be measured throughout the test. At end of every stage of LDDSE, the following measurements should be done:

  1. LVOT VTI by PW Doppler
  2. SV and SVi to BSA
  3. Aortic VTI by CW Doppler (the maximal aortic jet was recorded from apical or right parasternal window)
  4. Aortic peak and mean gradient
  5. TVFLR (SV/ET)
  6. Aortic acceleration time/ET
  7. Aortic valve area (AVA) and AVA indexed to BSA by continuity equation
  8. Cardiac output (CO) (Stroke volume x Heart rate)
  9. Projected AVA if the target of TVFLR >250 ml/s is not achieved.


The contractile reserve in classical LF/LG AS is estimated by increase in SV and TVFLR at peak dobutamine. The CR+ve is defined as SV increase >20% from baseline, CO increase >5 l/min, and TVFLR >200 ml/s. CR−ve is defined as no increase or increase in SV, CO, and TVFLR less than the respective cutoff values. The differentiation of true- or pseudo-severe AS in patients with CR+ve response is detailed in [Table 1]. The patients with CR−ve response are further studied by projected AVA, CT calcium scoring, and biomarkers. The true-severe AS is more likely if CT calcium score of the valve >2000 AU in men or >1200 AU in women.[9]
Table 1: Differentiation of true severe aortic stenosis versus pseudo-severe aortic stenosis

Click here to view


For paradoxical LF LG AS, the nitroprusside infusion is started at 0.5 μg/min/kg and increased at 0.5–1.0 μg/min/kg every 5 min till maximal dose of 10 μg/kg/min or increase in aortic valve mean gradient >40 mmHg or fall in BP or the development of intolerable symptoms.[16] There is no 2D echo/Doppler study to validate this approach for differentiation of pseudo- versus true-severe AS in paradoxical LF LG AS.


  Examples of Low-Dose Dobutamine Stress Echocardiography in Low-Flow Low-Gradient Aortic Stenosis Top


Case A

A 81-year-old male presented with shortness of breath, BP 165/70 mmHg, BSA 1.78 m 2, known ischemic heart disease, and LVEF = 25%. The 2D echo/Doppler [Figure 2]a and [Figure 2]b shows aortic peak/mean gradient 43/27 mmHg, LVOT = 20 mm, SV = 28 ml/m 2, AVA = 0.73 cm 2, and TVFLR = 186 ml/s. The LDDSE data are shown in [Table 2]. The data show that at peak dose of dobutamine, the SV has increased by 30% and the TVFLR has crossed 250 ml/s suggesting CR+ response. The mean gradient has reached 40 mmHg, and the AVA has increased by 0.09 cm 2 to 0.82 cm 2. These data suggest true-severe AS in the presence of CR+ve classical LF/LG AS.
Figure 2: (a and b) Case A: Two-dimensional transthoracic echo/Doppler tracings (a) resting (b) at peak low-dose dobutamine stress echocardiography 15 μg/kg/m

Click here to view
Table 2: Low-dose dobutamine stress echocardiography data of case A, a case of classical low-flow low-gradient aortic stenosis

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Case B

A 75-year-old male presented with a history of easy fatigability and dyspnea with day-to-day activities, BP 110/70 mmHg, BSA 1.7 m 2, not known ischemic heart disease, and LVEF = 28%. The 2D echo/Doppler [Figure 3]a and [Figure 3]b shows aortic peak/mean gradient 42/24 mmHg, LVOT = 22 mm, SV = 29 ml/m 2, AVA = 0.78 cm 2, and TVFLR = 166 ml/s. The LDDSE data are shown in [Table 3]. The data show that at peak dose of dobutamine, the SV has increased by 40% and the TVFLR has reached 345 ml/s suggesting CR+ve response. The mean gradient has reached 32 mmHg, and the AVA has increased by 0.42 cm 2 to 1.2 cm 2. These data suggest pseudo-severe AS in the presence of CR+ve classical LF/LG AS.
Figure 3: (a and b) Case B: Two-dimensional transthoracic echo/Doppler tracings (a) resting (b) at peak low-dose dobutamine stress echocardiography 20 μg/kg/min

Click here to view
Table 3: Low-dose dobutamine stress echocardiography data of Case B, a case of classical low-flow low-gradient aortic stenosis

Click here to view


Case C

A 70-year-old male presented with a history of CHF, BP 130/80 mmHg, BSA 1.7 m 2, not known ischemic heart disease, and LVEF = 24%. The 2D echo/Doppler [Figure 4]a and [Figure 4]b shows aortic peak/mean gradient 52/32 mmHg, LVOT = 20 mm, SV = 30 ml/m 2, AVA = 0.58 cm 2, and TVFLR = 156 ml/s. The LDDSE data are shown in [Table 4]. The data show that at peak dose of dobutamine, the SV has reduced by 15% and the TVFLR has reached 184 ml/s suggesting CR−ve response. The mean gradient has reached 37 mmHg and the AVA has increased by 0.06 cm 2 to 0.64 cm 2. If the AVA data (Y-axis) are plotted against TVFLR (X-axis), at each stage of LDDSE, then we can project the slope line of the graph (representing valve compliance) to the target value of 250 ml/s [Figure 5]. The Y-intercept at the target TVFLR, the projected AVA, is 0.78 cm 2. These data suggest true-severe AS in the presence of CR-ve classical LF/LG AS.
Figure 4: (a and b) Case C: Two-dimensional transthoracic echo/Doppler tracings (a) resting (b) at peak low-dose dobutamine stress echocardiography 20 μg/kg/min

Click here to view
Table 4: Low-dose dobutamine stress echocardiography data of case C, a case of classical low-flow low-gradient aortic stenosis

Click here to view
Figure 5: Low-dose dobutamine stress echocardiography data of Case C, a case of CR − ve classical low-flow low-gradient aortic stenosis. Aortic valve area in square centimeter (Y-axis) plotted against transvalvular flow rate in ml/s (X-axis) for each stage of low-dose dobutamine stress echocardiography

Click here to view



  The Relevance of Low-Dose Dobutamine Stress Echocardiography in the Transarterial Aortic Valve Replacement Era Top


The advent TAVR had abrupt and disruptive effect on the way we manage elderly patients of AS with serious comorbidities or patients with CR+ve or CR−ve LF/LG AS. Compared to surgical AVR, the periprocedural risk of morbidity and mortality is significantly reduced with TAVR in the high-risk group of paradoxical LF/LG AS and classical LF LG AS with or without CR. In the TOPAS-TAVI registry, TAVR in classical LF LG AS showed no correlation of preprocedural CR detected by LDDSE and postprocedure improvement in LVEF at 1 year and event-free survival at 2 years.[24] Nevertheless, the so-called pseudo-severe AS may represent a group of patients with moderate but progressive calcific AS and early-onset LV dysfunction without benign prognosis. A TAVR trial (TAVR unload) is underway to establish the benefit of TAVR in this group of patients. These issues raise doubts about the role of LDDSE in LF/LG AS in the modern era of TAVR.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgement

The article is being republished for wider dissemination of research outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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