In this study, 1,391 patients with baseline ECG with AVA < 1 cm² and normal LVEF from 14 tertiary hospitals (Figure 1), mean age 74.5 (10.9) years and 53.6% women were included. In the whole cohort, 752 (54.1%) were classified as HG, 492 (35.4%) as NFLG, and 147 (10.5%) as LFLG. No significant differences were observed among groups regarding age, sex, or cardiovascular risk factors, except for smoking and body weight (Table 1). The mean total follow-up time was 59.0 months (IQR 39.7–82.9 months), with no significant differences among groups.

The echocardiographic data of each AS subtype are shown in Table 2. Remarkably, AVA of the LFLG group was similar to AVA of the HG group [0.74 (0.14) vs. 0.73 (0.16) cm²; p = NS] and significantly lower than that of the NFLG group [0.89 (0.09), p < 0.001]. However, the dimensionless index (ratio between LVOT VTI and aortic VTI) value in the LFLG group was intermediate between the HG group [0.25 (0.06) vs. 0.22 (0.05); p < 0.001] and the NFLG group [0.25 (0.06) vs. 0.27 (0.04); p < 0.001], with differences between the HG and NFLG groups also being significant [0.22 (0.05) vs. 0.27 (0.04); p < 0.001]. Left ventricular hypertrophy was significantly lower in patients of the LFLG group compared with the HG group and similar to the NFLG group (Table 2). Severe valve calcification in the LFLG group was lower than in the HG group and showed no significant differences with the NFLG group.

In total, 1,248 patients had complete data related to AVR (676 (54.2%) with HG, 450 (36.0%) with NFLG and 122 (9.8%) with LFLG). Throughout the follow-up, 857 patients (68.7%, CI 95% 66.0–71.2) underwent AVR [685 surgery and 172 Transcater Aortic Valve Implantation (TAVI)]: 529 with HG (78.2%, CI 95% 75.0–81.3; median time: 17.7 months, IQR 5.5–43.4 months), 74 with LFLG (60.6%, CI 95% 51.4–69.4; median time: 41.0 months, IQR 13.6–78.9 months) and 254 with NFLG (56.4%, CI 95% 51.7–61.1; median time: 46.9 months, IQR: 26.0–70.0 months) (Figure 2) with differences among groups in the estimated survival free from AVR that persisted after adjustment for age, smoking, diabetes mellitus, presence of symptoms, and LVEF (p < 0.001). In HG AS, AVR was indicated earlier compared with NFLG (log-rank p < 0.001) and LFLG AS (log-rank p < 0.001). No significant differences were observed between the LFLG and NFLG groups (log-rank p = 0.358).

On multivariate analysis, indication of AVR was inversely associated with age (hazard ratio [HR] 0.99, CI 95%: 0.98–0.99; p = 0.002); nevertheless, the presence of symptoms (HR 1.82, 95% CI: 1.57–2.01; p < 0.001) and coronary artery disease (HR 1.21, 95% CI: 1.03–1.43; p = 0.018) were independently related to AVR indication. Regarding echocardiographic parameters, AVA (AVA < 0.8 cm²: HR 1.25, 95% CI: 1.04–1.48; p = 0.014), mean gradient (mean gradient ≥ 40 mmHg: HR 1.95, 95% CI: 1.67–2.29, p < 0.001), dimensionless index (dimensionless index ≤ 0.25: HR 1, 39, 95% CI: 1.18–1.65, p < 0.001), and LVEF 50–55% (HR 1.52, 95% CI: 1.21–1.91, p < 0.001) were also independently associated to AVR indication (Supplementary Table 1).

Overall mortality during follow-up was 27.7% (385 patients, CI 95% 25.3–30.1): 46 of the LFLG group (31.3%, CI 95% 23.9–39.5; median time: 50.8 months, IQR: 29.6–75.8), 205 of the HG group (27.3%, CI 95% 24.1–30.6; median time: 56.1 months, IQR: 33.8–83.7), and 134 of the NFLG group (27.2%, CI 95% 23.3–31.4; median time: 53.2 months, IQR: 31.0–76.9). Kaplan–Meier survival curves showed no significant differences among groups (Figure 3, log-rank p = 0.319). Early mortality after AVR (<30 days) was 6.5% (25 patients, CI 95% 1.2–2.6) with no differences among groups.

Death from cardiovascular cause occurred in 195 cases (14%, CI 95% 12.2–16.0) representing a 50.6% of overall mortality: 28 patients with LFLG (19%, CI 95% 13.0–26.3; median time: 50.9 months, ICR: 32.0–75.9), 95 patients with HG (12.6%, CI 10.3–15.2; median time: 56.1 months, ICR: 33.8–83.7), and 72 patients with NFLG (14.6%, CI 95% 11.6–18.1; median time: 52.5 months, ICR: 29.0–76.9), with no significant differences among groups (Figure 4, log-rank p = 0.061).

In patients undergoing AVR, no significant differences in mortality were observed among groups (log-rank p = 0.612) after adjustment for significant clinical variables and AVA. However, in non-operated patients, differences were observed among groups (log-rank p = 0.004), with low event-free survival in the HG group compared with the NFLG group (log-rank p = 0.001), with no significant differences between the LFLG and HG groups (log-rank p = 0.354) or between the LFLG and NFLG groups (log-rank p = 0.171).

In the multivariate analysis, age (HR 1.06, 95% CI: 1.04–1.08; p < 0.001), diabetes mellitus (HR 1.52; 95% CI: 1.23–1.89; p < 0.001), smoking (HR: 1.77, 95% CI: 1.32–2.37; p < 0.0001), COPD (HR 1.45, 95% CI: 1.09–1.92; p = 0.010), and the presence of symptoms (HR 1.48, 95% CI: 1.18–1.85; p = 0.001) were clinical variables associated to overall mortality (Supplementary Table 2). Echocardiographic variables independently associated with mortality were mean gradient > 50 mmHg (HR 1.56, 95% CI: 1.17–2.08; p = 0.002) and LVEF 50–55% (HR 1.68, 95% CI: 1.07–2.63; p = 0.023).

Overall mortality was higher in those patients who did not undergo AVR. The impact of AVR on mortality reduction in the whole population with AS was significant (HR: 0.22; 95% CI: 0.18–0.28; p < 0.001) after adjustment for significant clinical variables and AVA. AVR reduced mortality risk by 83% in patients with HG AS (HR: 0.17; 95% CI: 0.12–0.23; p < 0.001), 75% in patients with LFLG (HR: 0.25; 95% CI: 0.13–0.49; p < 0.001), and 71% in patients with NFLG AS (HR: 0.29; 95% CI: 0.20–0.44; p < 0.001; Figure 5).

In the present series, patients with LFLG AS had a similar AVA value to the HG group and lower than NFLG group. However, in the remaining echocardiographic parameters, such as left ventricular hypertrophy and degree of valve calcification, LFLG did not significantly differ from NFLG AS. Interestingly, the dimensionless index in LFLG AS laid between HG and NFLG AS. Thus, LFLG AS presented intermediate-severity echocardiographic parameters between HG and NFLG AS. Other series yielded similar results (4). Clavel et al. in a series of 561 patients with AS, found LFLG patients to have significantly lower velocity and transaortic gradients than HG AS while AVA was practically the same (11). Several studies reported that this entity was associated with small ventricles and a high degree of hypertrophy (2); however, the present LFLG group had a significantly lower degree of hypertrophy than patients with HG AS but similar to those with NFLG AS. Other studies using echocardiography or CMR stated that patients with LFLG AS do not have a greater degree of hypertrophy than HG AS, but lower or similar to NFLG AS or moderate AS (4, 5, 12). Few studies analyzed the degree of calcification in LFLG AS by echocardiography or multidetector CT (MDCT), although this is currently one of the more recommended approaches to diagnose severe AS (10, 13). Calcification by MDCT may be highly useful in patients with discordant severity data on echocardiography (13).

The risk throughout follow-up of undergoing AVR was higher for patients with HG, lower in patients with LFLG AS and comparable to patients with NFLG AS, as previously reported (14). Mortality was 27% and no significant differences were detected between patients with LFLG AS and the other groups. Patients of the three hemodynamic groups who underwent AVR had a similar prognosis, whereas patients who did not undergo surgery had higher mortality in the HG group compared with the NFLG group, with no differences between the LFLG and HG groups. Different series previously reported poorer survival and a higher rate of events in the LFLG population compared with HG AS (3, 11, 15); however, the trend in the more contemporary series has changed the paradigm, suggesting that higher mortality is associated with HG AS, with the behavior of LFLG AS being more similar to moderate AS or intermediate between HG and NFLG AS (8, 16). Recent evidence suggested that moderate forms of AS are not as benign as historically assumed, particularly if left ventricular dysfunction is present (17). A recent study analyzing data from the Australian national echocardiography database showed mortality in patients with moderate AS to be similar to severe AS (18). Another contemporary study reported that patients with NFLG who did not undergo surgery had 6.3 times more overall mortality compared with surgically-treated patients, with surgery being associated with a significant increase in survival (19). Taking the results of this study and previous reported findings into account, there may be sufficient reasons to consider AS severity as moderate-severe when the AVA is between 0.8–1.2 cm² and severe when < 0.8 cm². In moderate-severe patients with AS, other multimodality parameters, such as calcium score by CT, exercise test, or left ventricle overall strain could help to identify a subgroup of patients in whom AVR would be indicated.

Overall, patients with significant AS benefited from intervention on the AV, and despite the HG AS group benefited the most, both LFLG and NFLG AS also obtained significant benefit. Although few studies failed to show this benefit in patients with LFLG AS (5, 20), most series suggested a beneficial effect of valve replacement in the LFLG population (and even in NFLG and moderate AS) compared with conservative management (4, 18, 19). Thus, evidence of the effectiveness of aggressive treatment (surgical or percutaneous) of AS continues to grow and, though data remain discrepant, the trend is toward a more aggressive approach and in a wider range of the disease.

In this study, patients with AS who died were older, more symptomatic, had more cardiovascular risk factors and a smaller AVA. However, the multivariate analysis failed to show AVA to be independently associated with mortality which instead was related to age, risk factors (diabetes, smoking, and COPD), symptoms, mean gradient > 50 mmHg, and LVEF from 50–54%. Some studies showed mortality in AS to be associated with maximum velocity, aortic calcification, and LVEF. Valvular heart disease guidelines recommended as class I an AVR indication in systolic dysfunction (LVEF < 50%) regardless of the presence of symptoms (9, 21). However, recent studies reported that patients with LVEF < 55% had poor prognosis (22–24). All these results suggest that the cut-off point of <50% for LVEF could be too low, indicating that left ventricular dysfunction is already present when LVEF is between 50 and 60% and, in fact, recent guidelines recommend that patients with LVEF <60% on serial studies and severe AS should undergo surgery (21). Cardiac magnetic resonance demonstrated the presence of late gadolinium enhancement and increased extracellular volume in AS patients with normal ejection fraction, which have been related to prognosis (25). Other imaging techniques, such as strain by speckle tracking echocardiography can detect patients with subclinical ventricular dysfunction, (26) with overall longitudinal strain values < −15% being associated with worse prognosis (27, 28). Global LV strain values may become one of the markers that will provide additional data to decide whether or not the patient could have a higher risk and deserves surgery. Given that patients with LFLG AS benefit significantly from AVR, they should be followed with caution, with the accuracy in echocardiographic severity evaluation to be maximized to avoid possible errors in SVi quantification. Furthermore, additional information through other imaging techniques (myocardial strain, CMR of calcium score by CT) are likely to be useful to determine whether data support the AS severity and/or suggest incipient ventricular dysfunction, to sustain the choice to treat paradoxical LFLG as HG AS.