Some observational data suggest that long-term prognosis in asymptomatic AS stenosis may not be as favorable as previously thought, suggesting that there exists a window of opportunity for intervention prior to the onset of symptoms. Recent data indicate that there is an increased risk of mortality in asymptomatic severe AS, even when LVEF is >50% ^[1][25]. Moreover, Banovic et al. ^[2][26] in the AVATAR trial demonstrated that, in asymptomatic severe AS, early surgery aortic valve replacement reduced the occurrence spontaneous follow-up events (death, acute myocardial infarction, stroke, acute heart failure) compared with conservative treatment, regardless of the symptoms concerned.

When exercise testing causes symptoms, the patient is deemed to be symptomatic and qualifies for an aortic valve replacement class 1 recommendation. Symptoms are considered symptoms if they are reported deliberately by the patient or detected by exercise testing. Normally, in patients without overt symptoms who exhibit (1) a drop of >10 mm Hg in systolic blood pressure from baseline to peak exercise or (2) a significant decrease in exercise tolerance compared to age and sex normal standards, the rate of symptom onset is elevated within the bounds of 1 to 2 years (roughly 60% to 80%) ^[3][27].

Therefore, guidelines recommend evaluating asymptomatic AS with exercise stress in physically active patients, particularly those younger than 70 years. A decreased exercise tolerance indicates intervention for the 2020 ACC/AHA ^[4][1] and 2021 ESC guidelines ^[5][2].

The 2021 ESC recommendations state that, if the resting LVEF is lower than 55% without evidence of an additional cause, intervention should be considered in patients with severe AS who are asymptomatic. Additionally, this is advised if the LVEF is less than 50% (class of recommendation 1) ^[5][2]. Given that underestimating symptoms is common in AS and that patients often limit their level of activity over time to cope with the disease’s slow progression, stress testing combined with exercise is helpful in identifying patients who are truly asymptomatic.

The incidence of the abnormal stress test in asymptomatic severe AS has ranged from 28% to 67%, with a pooled average of 49% ^[6][28]. A lower % of age–sex–predicted metabolic equivalents and slower heart rate recovery are associated with long-term mortality. If patients prove to have a preserved exercise capacity, a safe deferral of surgery is proposed for the next 1 year ^[7][29].

Therefore, recording abnormal aortic valve hemodynamics with exercise echocardiography is of limited additive value and is no longer recommended for decision making.

The predictive value of the test is diminished in older adults despite the fact that a negative exercise test result may seem comforting in younger patients. Combining them with the echocardiographic evaluation of LV function, transvalvular pressure gradients and pulmonary arterial pressure can be useful.

In this case, the application of ABCDE SE in asymptomatic AS patients has the potential to identify the presence of latent coronary artery disease (Step A+); the presence of B lines at peak stress (Step B+), indicative of a preclinical decompensation which may precede the onset of dyspnea and symptoms by days or months; a latent LV dysfunction with reduced LV CR (Step C+); and an impaired coronary flow velocity reserve (Step D+). This is particularly the case in in patients who have angiographically normal coronary arteries and severe AS. When a valve is replaced prior to the regression of LV hypertrophy in these patients, the degree of coronary microvascular disease, which is reflected in a reduction in coronary flow reserve during stress testing and is related to exercise capacity, is reversible and foresees outcomes better than the severity of AS ^{[8][9][10][11][12]}[30,31,32,33,34]. Therefore, it is well established that coronary microcirculation is impaired in AS, impacting myocardial remodeling, aortic flow patterns, and clinical progression ^[13][35].

There are invasive and more reproducible invasive tests to assess absolute coronary flow and coronary flow reserve in patients with severe AS candidate to TAVI/SAVR. In patients with severe AS and non-obstructive coronary artery disease, an invasive study demonstrated that the compensatory mechanism of increased resting flow maintains adequate perfusion at rest, but not during hyperemia, with a consequent reduction in coronary flow reserve ^[14][36].

The management of patients with moderate AS is very important, particularly in terms of the choice between early intervention versus watchful waiting. The correct diagnosis of true moderate AS is of primary importance. For an accurate measurement of the trans-aortic jet velocity, multiple acoustic windows should be used in order to determine the highest velocity, In fact, alignment errors in the Doppler beam led to an underestimation of the true velocity, and consequently to the calculated gradients underestimating AS severity. In addition, an echocardiographic evaluation of valve morphology and aortic valve calcium scoring can be performed using computer tomography (CT) to confirm the diagnosis of true moderate AS. Paolisso et at. ^[15][37] demonstrated that the heart valve clinic approach, within a multidisciplinary team, is associated with better management in moderate AS in relation to diagnostic tests, education, and treatment. Additionally, this approach was shown to be an independent predictor of reduced all-cause death in patients with moderate AS.

The evaluation of classical LFLG AS is the main indication of SE in valvular heart disease ^[16][38]. Classical LFLG AS is defined as a mean gradient < 40 mmHg, valve area ≤ 1 cm², LV EF < 50%, and stroke volume index ≤ 35 mL/m².

Due to the difficulty of separating patients with severe AS from those who have pseudo-severe AS, this entity poses a diagnostic challenge ^{[4][5][17][18]}[1,2,9,39]. The small area of the aortic valve plays a role in the severity of AS by increasing afterload, decreasing LVEF, and decreasing cardiac output. In pseudo-severe AS, the severity of the condition is overstated because the underlying LV systolic dysfunction reduces the opening force, causing an incomplete valve opening ^[19][40]. In patients with classical LFLG AS, low-dose dobutamine SE (up to 20 mcg/kg/min) is recommended by ESC guidelines (class 1), and it may be helpful to determine the trans-valvular gradient and the AVA to differentiate severe (true AS) from pseudo-severe AS ^{[17][18][19][20][21]}[9,13,39,40,41].

The primary objective of using dobutamine SE is to boost the transvalvular flow rate without causing myocardial ischemia. In response to an increase in transvalvular flow rate, patients with pseudo-severe AS will have an increase in the AVA and little change in gradient, whereas patients with severe AS will possess a fixed valve area but undergo an increase in stroke volume and gradient ^{[5][17][18][19][20]}[2,9,13,39,40]. Therefore, it is considered reasonable to use low dose dobutamine SE to define severity further and assess CR with the ACC/AHA 2020 guidelines ^[4][1].

Evaluation of the LV CR is a critical component of classical LF-LG AS because patients with reduced LV CR have a higher risk of unfavorable events ^[17][18][20][9,13,39]. The imaging assessment is based on the assessment of flow reserve (an increase in stroke volume of at least 20%) and LV systolic function (changes in EF or global longitudinal strain) ^[17][18][20][9,13,39], an analysis of changes in pressure gradients, and AVA. An increase in stroke volume >20% denotes significant LV CR ^[18][19][39,40].

An imbalance between the severity of the stenosis and myocardial reserve, an inadequate increase in myocardial blood flow because of associated coronary artery disease, irreversible myocardial damage from a previous myocardial infarction or extensive myocardial fibrosis can all contribute to the lack of stroke volume increase during dobutamine SE ^[16][38].

A noninvasive method of assessing LV CR can be inferred to add another modality ^[21][22][23][41,42,43] because changes in LV force are a load-independent measure of left ventricular contractility. The enhancement in LVEF is typically used to assess LV CR. However, it depends on heart rate, preload, afterload, synchrony of contraction, and other factors to combined to generate myocardial contractility, which may occasionally even be deceptive ^[22][42].

The LV CR measured by LV force, however, significantly varies from LVEF when the situation is viewed from a conceptual, methodological, and clinical perspective. It only requires the measurement of systolic blood pressure by cuff sphygmomanometer and end-systolic volume by 2D echocardiography, rather than the assessment end-diastolic and end-systolic volume. It is independent of preload and afterload changes ^[23][43], which instead affect LVEF.

Additionally, with all modalities of SE, LV CR is more prognostically effective than LVEF changes in identifying patients at higher risk, including both those with normal and those with noticeably abnormal resting LV function ^[24][25][26][44,45,46]. Systolic blood pressure should be added to the peak AV gradient in AS patients to evaluate LV force.

Patients with an increased indexed stroke volume of at least 20%, an unchanged AVA, and an unchanged transvalvular gradient have indeterminate AS severity. Up to 30% of patients lack CR, indicating a high risk of perioperative mortality following surgical aortic valve replacement ^[27][28][48,49]. Projected AVA (AVAProj) at a typical transvalvular flow rate has been suggested as a new parameter with which to obtain this significant limitation.

This parameter’s goal is to predict the AVA would be at a standard normal flow rate of 250 mL/s. When compared to conventional DSE parameters, it has been discovered that in patients with LG-AS, the AVAProj more accurately foresees underlying AS severity, the impairment of myocardial blood flow, LV pump reserve, and survival ^[29][50]. Thus, the AVAProj has the potential to elevate the diagnostic precision of DSE to being able to differentiate between severe and pseudosevere AS.

In discordant severe AS, the confirmation of the actual AS severity is essential. Both the American and European guidelines recommend performing non-contrast CT to quantitate aortic valve calcification and therefore differentiate true severe vs. non-severe AS, and this is particularly true in the case of patients with paradoxically low flow and LG-AS. Additionally, CT cut-offs have been defined to identify patients who likely have an AVA <1 cm^{2 [4][5]}[1,2]. However, at present, no prospective studies have used CT calcium scoring to help identify true severe AS amongst a cohort in which the results of CT findings guided aortic valve intervention.

In patients with classical LF-LG AS, severe impairment of LV longitudinal systolic function at rest or during dobutamine SE, very low LVEF (35%), and the absence of LV CR are the main factors that have been linked to an increased risk of mortality under conservative management, as well as following aortic valve replacement ^{[17][20][27][28][29]}[9,13,48,49,50].

SE has an important diagnostic and prognostic role in evaluating LV CR patients with heart failure patients and reducing LV EF ^[30][31][52,53].

The prognostic role of LV CR for AS patients who are candidates for transfemoral aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) remains to be clarified ^[30][32][51,52].

In LF-LG AS patients undergoing SAVR, the peri-procedural risk is considered greater if LV CR is absent ^[21][41].

Patients with LV CR have a significantly better results with percutaneous or surgical aortic valve replacement than with medical therapy in LF-LG traditional severe AS ^{[21][22][28][29]}[41,42,49,50]. Aortic valve replacement surgery has a high operative mortality rate (6–33%) and can be associated with the absence of LV CR during dobutamine SE in about one-third of patients ^[28][29][49,50]. This factor does not, however, predict the absence of LV function improvement, the overcoming of symptomatic status, or late survival afterwards surgery ^[28][29][49,50].

However, the outcome and management of classical LFLG AS has changed: the operative outcome of SAVR has improved in LF-LG AS, with much lower operative mortality and less frequent severe prosthesis–patient mismatch ^[33][34][35][54,55,56]. TAVI has emerged as a valuable alternative to SAVR due to the less invasive nature of the procedure, the lower requirements of postoperative care, and the superior toleration of the percutaneous procedure altogether by the patient ^[34][36][55,57].

The prognostic role of SE in LF-LG AS remains uncertain and needs to be clarified with further scientific evidence. Ribeiro et al. ^[37][58] showed that the absence of LV CR was not associated with any adverse effect on clinical outcomes or LVEF changes at follow-up. The same results were found by Buchanan et al. ^[38][59], who did not find differences in all-cause mortality in the presence or absence of LV CR in LF-LG AS; Sato et al. ^[39][24] and Maes et al. ^[40][60] confirmed that the absence of LV CR had no effect on clinical outcomes or changes in LVEF over time. Annabi et al. ^[41][61] demonstrated that in patients with classical LFLG AS produced excellent outcomes at one year following TAVI, regardless of the presence or absence of LV CR at preprocedural dobutamine SE.

Conversely, when working on LFLG AS patients undergoing TAVI, Barbash et al. ^[42][62] showed that CR that was assessed with dobutamine SE did not predict LVEF recovery but was associated with lower mortality ^[43][21]. Similarly, Hayek et al. ^[44][63] showed that in LFLG AS patients without LV CR had worse survival than those with LV CR. Finally, D’Andrea et al. ^[45][64] showed that LV CR, assessed by global longitudinal strain during dobutamine SE, was associated with significant LV reverse remodeling after the TAVI procedure.

Based on this evidence, the current ESC guidelines ^[5][2] suggest that intervention should be considered in LF-LG AS patients with reduced LVEF without LV CR, mainly when cardiac CT calcium scoring confirms severe aortic stenosis with a class of recommendation IIa; for LF-LG AS patients with reduced LVEF and evidence of LV CR, ESC guidelines suggest intervention with a higher class of recommendation (Ib).

AS is a common valvular disease, especially affecting the elderly. As for atrial fibrillation, the incidences of this issue increase with age. Many studies in different subgroups of AS have shown that atrial fibrillation is associated with worse outcomes ^[46][47][48][65,66,67]. In fact, atrial fibrillation is a marker of underlying structural abnormalities: LV hypertrophy, LV diastolic dysfunction, and left atrial dilatation, each of which can be associated with atrial fibrillation ^[48][49][67,68]. Atrial fibrillation, precipitating symptom onset, may play an important role in the clinical course of the AS ^[49][68].

Finally, AS should be considered in the bleeding risk assessment of patients with atrial fibrillation with an increased risk of gastrointestinal bleeding ^[50][69].