Low-Flow Low-Gradient Aortic Stenosis: When is it Severe?
A low flow state may occur with reduced left ventricular ejection fraction (LVEF) (i.e. Classical Low Flow) or with preserved LVEF (i.e. Paradoxical Low Flow) and it is often associated with a low transvalvular gradient given that the gradient is highly flow-dependent1, 2. In both types of low-flow, low-gradient (LF-LG), classical or paradoxical, it is difficult, from the resting echocardiographic exam, to differentiate a true-severe from a pseudo-severe stenosis. This distinction is nonetheless essential given that patients with true-severe AS generally benefit from aortic valve replacement (AVR), whereas those with pseudo-severe stenosis should be treated medically (Slide #1)3. Additional diagnostic tests such as dobutamine stress echocardiography (DSE) and aortic valve calcium scoring by multidetector computed tomography (MDCT) may be used to distinguish true- from pseudo- severe AS.
CLASSICAL LF-LG AS WITH REDUCED LVEF
This entity is found in about 5-10% of the patients with severe AS2 and it is characterized by a reduced LVEF (<50%) and a discordance between the aortic valve area (AVA<1 cm2 and/or <0.6 cm2/m2, consistent with severe AS) and the mean gradient (MG<40 mmHg, consistent with non-severe AS) (Slide #2). In a low flow state, the gradient may be pseudo-normalized and thus underestimate the stenosis severity, whereas the AVA may be pseudo-severe and thus overestimate the severity.
Dobutamine stress echocardiography
A low dose (up to 20μg/kg/min) DSE is useful to differentiate true- versus pseudo- severe AS (Slide #2)4. Typically, true-severe AS shows little or no increase in AVA and substantial increase in gradient, which is congruent with the relative increase in flow, whereas pseudo-severe AS shows a marked increase in AVA and little or no increase in gradient in response to increasing flow. Accordingly, in the 2014 ACC/AHA guidelines3, there is a class IIa indication for AVR in symptomatic patients with classical LF-LG AS if they show a mean gradient ≥ 40 mmHg and an AVA≤1.0 cm2 at any dobutamine stage (Slide #1).
However, several patients have incomplete normalization of flow with DSE and may thus still have discordant AVA-gradient findings at the end of DSE: i.e. a peak stress gradient < 40 mmHg with a peak stress AVA< 1.0 cm2. In such situation, one can calculate the projected AVA at normal flow rate (AVAProj), which provides an estimate of what would be the AVA at a normal transvalvular flow rate (i.e. 250ml/s)5, 6. This parameter is calculated as follows: AVAProj = AVARest + (ΔAVA/ ΔQ) × (250 - QRest), where AVARest and QRest are the AVA and Q (stroke volume / LV ejection time) at rest and ΔAVA and ΔQ are the absolute increases in AVA and Q during DSE. The best cutoff value to identify true severe AS is an AVAProj ≤ 1.0 cm2. The AVAProj has been shown to be superior to the traditional parameters of AS severity proposed in the guidelines to assess the actual AS severity as well as to predict outcomes5, 6. The calculation of the AVAProj is thus helpful when the AVA-gradient discordance persists at the end of DSE. However, a minimum of 15% increase in flow is required to obtain a reliable estimate of this parameter. In patients with no or minimal increase in stroke volume and flow rate (i.e. patients with no flow reserve), DSE generally remains non-conclusive and other imaging modalities, such as MDCT, are required to differentiate true- versus pseudo- severe stenosis (Slide #2).
Multidetector computed tomography
Aortic valve calcium scoring by MDCT is useful to corroborate stenosis severity when DSE is not feasible or not conclusive7, 8. MDCT has the advantage of being independent of hemodynamics/flow and is applicable to all patients. Moreover, calcium scoring does not require the injection of contrast agents. Recent studies showed that lower cutoff values of aortic valve calcium score should be used in women (≥1200 AU) than in men (≥2000 AU) to identify true severe AS and predict mortality (Slide #2)8, 9.
PARADOXICAL LF-LG AS WITH REDUCED LVEF
Paradoxical LF-LG AS occurs in 5-15% of patients with AS2 and it is defined as a preserved LVEF (≥50%), a low LV outflow (i.e. stroke volume index <35 mL/m2), a small AVA (≤1 cm2 and ≤0.6 cm2/m2), and a low gradient (<40 mmHg) (Slide #3)2, 3. In these patients, the low flow state is generally related to a pronounced LV concentric remodeling with impaired LV filling, and reduced systolic global longitudinal strain (despite normal LVEF)1, 2, 10, 11. Other factors may also contribute to the reduced stroke volume in the context of a preserved LVEF including: atrial fibrillation, concomitant mitral regurgitation, tricuspid regurgitation, or mitral stenosis etc. In the ACC/AHA guidelines3, a new class IIa indication of AVR was included for patients with paradoxical LF-LG AS if they are symptomatic, normotensive and the clinical, anatomical, and hemodynamic factors support the presence of a severe stenosis as the most likely cause of symptoms (Slide #1). This recommendation further emphasizes the importance of confirming the stenosis severity in these patients.
In patients with paradoxical LF-LG AS who are hypertensive, it is first recommended to initiate or optimize anti-hypertensive therapy and reassess symptoms and echocardiographic parameters of flow and stenosis severity, once blood pressure is normalized (Slide #3)3. As in patients with classical LF-LG AS, a low dose DSE or exercise stress echocardiography (in presence of mild or ambiguous symptoms) may also be used in patients with paradoxical LF-LG to differentiate true- versus pseudo- severe stenosis and the same parameters and criteria of AVA, MG, and AVAProj can be applied to these patients12. However, DSE is often not feasible or not conclusive in patients with paradoxical LF-LG AS, and particularly in those with severe restrictive physiology and/or concomitant mitral regurgitation. Hence, aortic valve calcium scoring by MDCT has become the modality of choice to confirm stenosis severity in these patients and one can used the same cut-point values of aortic valve calcium score (≥1200 AU in women and ≥2000 AU in men) as those described above for classical LF-LG AS (Slide #3)8,9.
LF-LG AS poses some important challenges with regard to confirmation of stenosis severity and therapeutic management. A low dose DSE is generally used to differentiate true- versus pseudo- severe AS and support the indication of AVR in patients with classical LF-LG who have significant flow reserve. The calculation of the AVAProj is helpful in situations where the AVA-gradient discordance and thus the uncertainty about stenosis severity persist at the end of DSE.
Aortic valve calcium quantification by MDCT may be helpful to distinguish true- from pseudo- severe stenosis in patients with classical LF-LG AS in whom there is no or minimal increase in flow during DSE and/or in whom the results of DSE are inconclusive. MDCT is also the modality of choice to confirm stenosis severity in patients with paradoxical LF-LG AS.
- Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. Paradoxical low flow, low gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation 2007; 115:2856-64.
- Pibarot P, Dumesnil JG. Low-flow, low-gradient aortic stenosis with normal and depressed left ventricular ejection fraction. J Am Coll Cardiol 2012; 60:1845-53.
- Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: Executive summary. A report of the American College of Cardiology/American heart association task force on practice guidelines. J Am Coll Cardiol 2014; 63:2438-88.
- deFilippi CR, Willett DL, Brickner E, et al. Usefulness of dobutamine echocardiography in distinguishing severe from nonsevere valvular aortic stenosis in patients with depressed left ventricular function and low transvalvular gradients. Am J Cardiol 1995; 75:191-4.
- Blais C, Burwash IG, Mundigler G, et al. Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low flow, low-gradient aortic stenosis: The multicenter TOPAS (Truly or Pseudo Severe Aortic Stenosis) study. Circulation 2006; 113:711-21.
- Clavel MA, Burwash IG, Mundigler G, et al. Validation of conventional and simplified methods to calculate projected valve area at normal flow rate in patients with low flow, low gradient aortic stenosis: the multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) study. J Am Soc Echocardiogr 2010; 23:380-6.
- Cueff C, Serfaty JM, Cimadevilla C, et al. Measurement of aortic valve calcification using multislice computed tomography: correlation with haemodynamic severity of aortic stenosis and clinical implication for patients with low ejection fraction. Heart 2011; 97:721-6.
- Clavel MA, Messika-Zeitoun D, Pibarot P, et al. The complex nature of discordant severe calcified aortic valve disease grading: New insights from combined doppler-echocardiographic and computed tomographic study. J Am Coll Cardiol 2013; 62:2329-38.
- Clavel MA, Pibarot P, Messika-Zeitoun D, et al. Impact of Aortic Valve Calcification, as Measured by MDCT, on Survival in Patients With Aortic Stenosis: Results of an International Registry Study. J Am Coll Cardiol 2014; 64:1202-13.
- Mehrotra P, Jansen K, Flynn AW, et al. Differential left ventricular remodelling and longitudinal function distinguishes low flow from normal-flow preserved ejection fraction low-gradient severe aortic stenosis. Eur Heart J 2013; 34:1906-14.
- Eleid MF, Sorajja P, Michelena HI, Malouf JF, Scott CG, Pellikka PA. Flow-gradient patterns in severe aortic stenosis with preserved ejection fraction: clinical characteristics and predictors of survival. Circulation 2013; 128:1781-9.
- Clavel MA, Ennezat PV, Maréchaux S, et al. Stress echocardiography to assess stenosis severity and predict outcome in patients with paradoxical low-flow, low-gradient aortic stenosis and preserved LVEF. J Am Coll Cardiol Img 2013; 6:175-83.
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