As many as 50% of patients with severe aortic stenosis (AS) report no symptoms at the time of diagnosis, and the optimal timing of intervention in these patients is controversial. This report reviews the natural history of patients with severe asymptomatic AS; summarizes the potential roles for exercise testing, biomarker assessment, and imaging to guide intervention; and reports results of a meta-analysis comparing early aortic valve replacement (AVR) with a more conservative approach of “watchful waiting” for asymptomatic patients with severe AS. The following are 10 points to remember:

1. Definitions and current recommendations. The current American Heart Association/American College of Cardiology (AHA/ACC) guideline describes four stages of AS; stages C and D refer to hemodynamically severe AS (defined as peak jet velocity [V_max] ≥4.0 m/s or mean gradient ≥40 mm Hg, or AV area ≤1.0 cm² or ≤0.6 cm²/m²). Stage C, describing asymptomatic severe AS, is divided into stages C1 (normal) and C2 (abnormal left ventricular [LV] systolic function, LV ejection fraction [LVEF] <50%). AVR currently should be performed for severe asymptomatic AS when the patient is undergoing another cardiac surgical procedure (Class I) or if valve-related symptoms are unmasked by stress testing (Class I); and AVR should be considered if AS is very severe (V_max ≥5.0 or 5.5 m/s [Class IIa]) or for an abnormal response to exercise (Class IIa).
2. Natural course of asymptomatic severe AS. Although on average V_max increases 0.3 m/s/year and AV area decreases 0.1 cm²/year, the rate of progression of severe AS is variable and unpredictable in individual patients. Within 5 years of diagnosis, approximately two-thirds of conservatively managed patients with asymptomatic AS will develop symptoms, and approximately 75% will have died or undergone AVR.
3. Predictors of symptom onset. More rapid symptom onset has been associated with increased hemodynamic severity of AS, the degree of AV calcification, abnormal stress test results, LV hypertrophy, baseline functional status, and comorbidities.
4. Sudden death risk in severe asymptomatic AS. The risk of sudden death among asymptomatic patients with severe AS is reportedly about 1%/year. However, once symptoms occur, as many as 3% of patients die suddenly within 3-6 months, and as many as 6.5% of symptomatic patients die while awaiting AVR; approximately 70% of sudden deaths among asymptomatic patients with severe AS occur with no preceding symptoms referable to AS.
5. Echocardiography in severe asymptomatic AS. Prognosis among patients with AS is related to echo/Doppler indices of hemodynamic severity including V_max, mean gradient, and valve area. In addition, a low-flow state (defined as stroke volume index <35 ml/m), dilated left atrium, reduced LVEF, LV hypertrophy, and pulmonary hypertension also have been associated with an adverse prognosis. Valvuloarterial impedance (Z_va, defined as the ratio of LV systolic pressure to the stroke volume index) and LV longitudinal strain are emerging as alternative markers for assessing the repercussions of AS on LV function.
6. Exercise testing in severe asymptomatic AS. An abnormal response to exercise is thought to reflect poor LV contractile reserve and an increase in transvalvular gradient and Z_va during exercise. Exercise-induced symptoms or an abnormal blood pressure response are predictive of worse outcome. The European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines (but not the AHA/ACC guidelines) include an increase in mean gradient (>20 mm Hg) during exercise stress imaging to help guide the management of asymptomatic patients with severe AS.
7. Computed tomography (CT) and cardiac magnetic resonance (CMR) in severe asymptomatic AS. CT and CMR imaging are increasingly used among patients with AS. Both techniques can provide detailed information on valve, aortic root, and aorta morphology; and are useful in preprocedural assessment before surgical or transcatheter AVR.
8. Biomarkers in severe asymptomatic AS. The ESC/EACTS guidelines (but not the AHA/ACC guidelines) include consideration for AVR among asymptomatic patients with severe AS and markedly elevated levels of natriuretic peptides, N-terminal pro-B-type natriuretic peptide, or the active hormone B-type natriuretic peptide (Class IIb).
9. Meta-analysis of AVR in severe asymptomatic AS. The authors performed a study-level meta-analysis of studies comparing AVR to a conservative approach among asymptomatic patients with severe AS. After considering 27 observational studies, four observational studies (including 2,486 patients) were analyzed. Pooled analysis suggested an approximate 3.5-fold higher rate of all-cause death associated with “watchful waiting” compared to early AVR. However, patients who were treated conservatively in general were older and sicker, stress testing was not performed to identify higher-risk patients, and systematic follow-up was problematic.
10. Authors’ recommendation for future testing. The authors suggest performance of a large-scale, prospective, randomized clinical trial to evaluate whether routine surgical or transcatheter AVR improves prognosis among asymptomatic patients with severe AS.

Keywords: Aortic Valve Stenosis, Biomarkers, Blood Pressure, Cardiac Surgical Procedures, Death, Sudden, Echocardiography, Exercise Test, Heart Failure, Hypertension, Pulmonary, Hypertension, Hypertrophy, Heart Valve Diseases, Magnetic Resonance Spectroscopy, Natriuretic Peptide, Brain, Peptide Fragments, Stroke Volume, Thoracic Surgery, Tomography, Tomography, X-Ray Computed, Transcatheter Aortic Valve Replacement, Ventricular Function, Left

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