The following are key points to remember from a review comparing the US and European guidelines for normal-flow low-gradient (NFLG) aortic stenosis (AS):

1. NFLG severe AS is defined as aortic valve area (AVA) ≤1.0 cm² (or AVA index ≤0.6 cm²/m²) with low gradient (mean gradient <40 mm Hg) and normal flow (left ventricular [LV] ejection fraction ≥50% and stroke volume index [SVI] ≥35 mL/m²), and occurs in approximately 20-30% of patients with severe AS.
2. Possible causes of NFLG severe AS include:
   • Echocardiography/Doppler measurement error (overestimation of SV, underestimation of mean gradient or LV outflow tract [LVOT] diameter, or not indexing AVA to body surface area [BSA]),
   • An imprecise definition of low flow based on SVI (without indexing SVI to LV ejection time [the transvalvular flow rate]),
   • Inherent inconsistencies of echo/Doppler parameters for the assessment of AS severity, and/or
   • The impact of systemic hypertension or reduced vascular compliance.
3. When there is discordance between the primary echo/Doppler parameters for the assessment of AS severity (mean gradient, peak velocity, and AVA) leading to a finding of NFLG severe AS, a stepwise approach might be helpful to determine the true severity of AS.
   • Ensure that systolic blood pressure is <140 mm Hg during diagnostic testing.
   • Exclude measurement error.
   • Index AVA to BSA.
   • Evaluate transvalvular flow rate (SV divided by LV ejection time). Prolonged ejection time or bradycardia can lead to a low-flow state (flow rate <200 mL/s) even in the setting of SVI ≥35 mL/beat/m².
   • Consider a multimodality evaluation with cardiac magnetic resonance imaging (MRI), multidetector computed tomography (MDCT), or cardiac catheterization (see below).
4. Multimodality evaluation of patients with NFLG severe AS can provide the following additional information:
   • Calcium score. Quantification of the aortic valve calcium score on MDCT is particularly helpful to confirm or refute a diagnosis of severe AS.
     • European Society of Cardiology/European Association for Cardiothoracic Surgery (ESC/EACTS) guidelines use tertiles to categorize sex-specific aortic valve calcium scores in terms of the likelihood of severe AS: men >3,000 or women >1,600, highly likely; men >2,000 or women >1,200, likely; men <1,600 or women <1,200, unlikely.
     • American College of Cardiology/American Heart Association (ACC/AHA) guidelines use a binary cutoff to define severe AS: men ≥2,000 and women >1,300.
   • LVOT area. MDCT and MRI provide an accurate measurement of LVOT area and can lead to reclassification of a large proportion of patients with NFLG AS. However, this is best reserved for patients with an obscured LVOT on echocardiography or echo LVOT diameter <1.8 cm.
   • Aortic valve gradients. Cardiac catheterization and MRI can provide accurate assessment of aortic valve gradients with Doppler angle errors encountered on echocardiography.
5. Studies on the natural history of patients with NFLG severe AS suggest:
   • Better survival compared to either patients low-flow low-gradient (LFLG) severe AS or high-gradient severe AS, and survival equivalent to patients with moderate AS.
   • Echo/Doppler parameters of AS progression that are similar to a general AS population (annual changes in peak velocity + 0.34 m/s, mean gradient + 6 mm Hg, and AVA – 0.06 cm²).
6. Studies on aortic valve replacement (AVR) in patients with NFLG severe AS include:
   • A meta-analysis of observational studies of AVR that showed a reduced risk of all-cause mortality compared to surveillance, with hazard ratios for AVR similar to patients with LFLG severe AS but higher than in patients with high gradient severe AS, suggesting a greater benefit of AVR among patients with high gradient AS.
   • Post hoc analysis of data from the PARTNER 1B trial that showed a survival benefit of transcatheter AVR (TAVR) compared to medical management in patients with NFLG severe AS.
7. Existing societal documents provide limited guidance for the management of patients with NFLG severe AS.
   • The 2021 ESC/EACTS guidelines indicate that patients with NFLG severe AS usually are clinically similar to patients with moderate AS and should be treated accordingly.
   • The 2017 European Association of Cardiovascular Imaging/American Society of Echocardiography (EACVI/ASE) focused update guidelines on AS also conclude that patients with NFLG severe AS typically have only moderate AS, but also suggest consideration for obtaining supportive data for decision making about AVR.
   • The 2020 ACC/AHA guidelines do not address patients with NFLG severe AS.
8. Outstanding questions remain regarding the optimal management of patients with NFLG AS:
   • For the diagnosis of NFLG severe AS:
     • What is the best threshold for normal flow versus low flow based on SVI?
     • Should SVI be indexed to LV ejection time (transvalvular flow rate)?
     • What is the optimal multimodality approach to the diagnosis of NFLG severe AS?
   • For the management of patients with NFLG severe AS:
     • There are limited trial data to guide intervention among patients with NFLG severe AS.
     • Ongoing trials on the management of patients with moderate AS might help inform management decisions for patients with NFLG severe AS.

Clinical Topics: Noninvasive Imaging, Valvular Heart Disease

Keywords: Aortic Valve Stenosis, Diagnostic Imaging

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