This is a single-center, retrospective cohort study conducted at The Christ Hospital, Cincinnati, OH under the approval of the Institutional Review Board (protocol ID 14-13: The Christ Hospital Structural Database); the need for informed consent was waived due to retrospective, observational nature of the study that did not impact patients’ care.

The echocardiography database (Merge, Inc, Las Vegas, NV, USA) was screened for those with moderate or less AS between September 2013 and August 2021, and the resulting group (n=997) was further screened in the electronic health record for brain natriuretic peptide (BNP) level >100 pg/mL within 6 months of the index echocardiogram (n=378). This step yielded 378 subjects. After 46 patients were excluded for inadequate echocardiography data, a total of 332 patients were eligible for the study. The moderate AS group (n=165) was compared with the rest of the group (none-mild AS, n=167). There was no specific creation of a control group or matching of baseline characteristics.

HFrEF is defined as the clinical diagnosis of HF with a left ventricular ejection fraction (LVEF) ≤50%, while HF with preserved ejection fraction (HFpEF) is defined as LVEF ≥50%.9) Patients with previous aortic valve surgery, a history of congenital heart disease, implanted left ventricular assist device, or a history of heart transplantation were also excluded. The following demographic and clinical variables were collected at a time point most proximate to the index echocardiogram: age, sex, body mass index, body surface area, hemoglobin, and serum creatinine. In addition, the presence of comorbidities (hypertension, diabetes, coronary artery disease, atrial fibrillation, chronic obstructive pulmonary disease, peripheral vascular disease, cerebrovascular accident, myocardial infarction), smoking history, and cardiac medications (antiplatelet agents, renin-angiotensin-aldosterone antagonists, calcium-channel blocker β-blocker, diuretic, statin) were recorded.

All patients underwent a comprehensive echocardiographic assessment using commercially available ultrasound systems (Philips IE33; Philips Ultrasound, Bothell, WA, USA). Left ventricular end-diastolic volume, left ventricular end-systolic volume, and LVEF were measured using the modified Simpson’s method. Transaortic peak velocity was obtained by continuous-wave Doppler echocardiography, and the pressure gradient was calculated using the simplified Bernoulli equation. Aortic valve area (AVA) was calculated using the continuity equation. The following echocardiographic parameters were also recorded: AVA (AVA-cm²), AVA index (cm²/m²), interventricular septal end-diastolic thickness (IVSd-mm), left ventricular internal diameter in end diastole (LVIDd-mm), left ventricular posterior wall end-diastolic thickness (PWd-mm), LVEF (%), peak and mean transaortic pressure gradients (mmHg), left atrial (LA) volume index (mL/m²), tricuspid annular plane systolic excursion (TAPSE-cm), E/A ratio, medial e’ velocity (cm/s), lateral e’ velocity (cm/s), E/e’ ratio, tricuspid regurgitation velocity (m/s), degree of aortic and mitral regurgitation. Echocardiographic indices were measured following the American Society of Echocardiography standards.10) Moderate AS was defined as AVA between 1 and 1.5 cm², peak trans-aortic velocity of 3.0–3.9 m/s, or mean pressure gradient of 20–39 mmHg.11) Those not meeting these criteria formed the none-mild AS comparator (control) group.

All patients’ records were reviewed from the date of the index echocardiogram until the death or the end of the study period. Clinical data were obtained by review of medical records, telephone interviews, and the social security database. The primary endpoint was the combination of all-cause mortality or all-cause hospitalization.

Continuous variables were presented as mean ± standard deviation (SD) for normal distributions, and median + interquartile range for non-normal distributions. Normality was tested using skewness, kurtosis, visual inspection of the histogram, and QQ plot. Categorical data were displayed as frequency (percentage), and comparisons between groups were performed using the chi-square test. As appropriate, continuous variable comparisons between groups were performed using the Student’s t-test or the Mann-Whitney U test. The Kaplan-Meier curve and log-rank test were computed to analyze all-cause mortality differences between moderate AS and control. For the Cox regression model, univariate analysis of each of the possible predictors of the outcome was tested, and only those variables that were significant at p<0.20 were included in a multivariate model to determine the independent predictors of the primary endpoint.12) However, age, gender, hemoglobin (Hgb), and baseline LVEF were included in multivariate analysis, regardless of univariate analysis results. The Poisson regression model was performed to examine the difference in hospitalization rates between groups. The hazard ratio (HR) and incidence rate ratio were presented as mean and 95% confidence interval (CI). A two-sided p value of <0.05 was considered statistically significant. The statistical analyses were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY, USA) and R software, version 4.0.3 (The R Foundation, Vienna, Austria).

A total of 332 consecutive patients (mean age of 75±14 years, 49.4% male) were included in our study. 165 patients (49.7%) had moderate AS, while 167 (50.3%) had none-mild AS and formed the control group. In the control group, 17 patients (10.2%) had no AS and 150 patients (89.8%) had mild AS. There were baseline differences between the two groups in the proportion of patients with a history of atrial fibrillation (42.1% in moderate AS vs. 31.3% in control, p=0.04). No other significant differences in comorbidities or cardiac medication were found between groups (p>0.05 for all, Table 1). Mean BNP levels were similarly elevated: 530 pg/mL (187–1004) in the moderate AS group vs. 518 pg/mL (182–945) in control, p=0.27).

Patients with moderate AS had lower LVEF (50.0±13.3% vs. 54.4±11.2%, p=0.001), and the proportion of those with LVEF <50% was higher in moderate AS (41.2%) than in control (28.1%) (p=0.01). Moderate AS group had lower TAPSE (1.7±0.5 cm vs. 2.0±0.7 cm, p<0.001), and higher TR velocity (2.9 m/sec [2.4–3.3] vs. 2.6 m/s [2.4–3.0, p=0.03] compared to control. Peak E velocity (103.0 [79.9–124.5] vs. 87.0 [68.0–114.0], p=0.001) and average E/e’ ratio (16.7 [13.0–22.5] vs. 14.9 [11.5–19.3], p=0.02) were significantly higher in moderate AS group when compared to control. Similarly, moderate AS patients also tended to have a larger LA volume index compared to the control, but the difference did not reach statistical significance (40.8 mL/m² [30.9–51.5] vs. 37.7 mL/m² [28.2–49.2], p=0.08). No major differences were found for the other echocardiographic indices (Table 2). During the median follow-up duration of 3.85 years (interquartile range: 3.04–5.77 years), 68 (41%) patients had one follow-up echocardiogram, and 42 (25.5%) had a second study in the moderate AS group. However, there was a significant variation in the time interval from the index echocardiogram to the first follow-up study: 0.5 years to 3.2 years.

Overall, in both groups, 61 (18.4%) patients died. The overall event rate for the primary composite endpoint of all-cause mortality or all-cause hospitalization was 64.2% (95% CI, 58.7–69.3%). Moderate AS had significantly higher rates of the primary endpoint than none-mild AS in both univariate analysis (HR, 1.50; 95% CI, 1.14–1.97; p=0.004) (Figure 1A), and adjusted analysis (HR, 1.45; 95% CI, 1.05–2.01, p=0.02) (Table 3). A significant mortality difference was observed between the two groups in univariate analysis (23.0% in moderate AS vs. 13.8% in control, χ²(1)=4.088, p=0.043, log-rank test; HR, 1.70; 95% CI, 1.01–2.86, p=0.046) (Figure 1B), although this difference did not reach statistical significance in multivariate analysis (Supplementary Table 1). When stratified into the HFrEF (n=115) and HFpEF (n=217) groups, the effect of moderate AS on mortality was similar between HFrEF (HR, 1.51; 95% CI, 0.71–3.22; p=0.29) and HFpEF (HR, 1.65; 95% CI, 0.80–3.41; p=0.17). Neither subgroup showed a statistically significant effect of moderate AS on mortality.

There was a total of 508 all-cause hospitalizations, with 299 in moderate AS and 209 in control. Using the Poisson regression model, moderate AS had 1.41 (95% CI, 1.18–1.69; p<0.001) times more all-cause hospitalizations per patient-year of follow-up compared with control (Figure 2). After adjustment for significant covariates (age, gender, coronary artery disease, atrial fibrillation, beta-blocker, calcium channel blocker, diuretics, hemoglobin, LVEF, LA volume index), moderate AS remained an independent predictor of all-cause hospitalizations (incidence rate ratio [IRR], 1.45; 95% CI, 1.18–1.79; p=0.005). Moderate AS was significantly associated with higher all-cause hospitalization rates in both HFrEF (IRR, 1.33; 95% CI, 1.02–1.75; p=0.038) and HFpEF [IRR], 1.31; 95% CI, 1.03–1.67; p=0.026) (Figure 2). There were 4 patients in the moderate AS group who underwent aortic valve replacement during the follow-up period.