Abstract
Aims
Current evidence on the prognostic value of exercise stress echocardiography (ESE) in asymptomatic patients with low-gradient severe aortic stenosis (AS) is limited. Therefore, this study aimed to elucidate its prognostic implications for patients with low-gradient severe AS and determine the added value of ESE in risk stratification for this population.
Methods and results
This retrospective observational study included 122 consecutive asymptomatic patients with either moderate [mean pressure gradient (MPG) < 40 mmHg and aortic valve area (AVA) 1.0–1.5 cm2] or low-gradient severe (MPG < 40 mmHg and AVA < 1.0 cm2) AS and preserved left ventricular ejection fraction (≥50%) who underwent ESE. All patients were followed up for AS-related events. Of 143 patients, 21 who met any exclusion criteria, including early interventions, were excluded, and 122 conservatively managed patients [76.5 (71.0–80.3) years; 48.3% male] were included in this study. During a median follow-up period of 989 (578–1571) days, 64 patients experienced AS-related events. Patients with low-gradient severe AS had significantly lower event-free survival rates than those with moderate AS (log-rank test, P < 0.001). Multivariable Cox regression analysis showed that the mitral E/e′ ratio during exercise was independently associated with AS-related events (hazard ratio = 1.075, P < 0.001) in patients with low-gradient severe AS.
Conclusion
This study suggests that asymptomatic patients with low-gradient severe AS have worse prognoses than those with moderate AS. Additionally, the mitral E/e′ ratio during exercise is a useful parameter for risk stratification in patients with low-gradient severe AS.
Keywords: Aortic stenosis, Low gradient, Exercise stress echocardiography, E/e′
Graphical Abstract
Graphical Abstract.
Introduction
Aortic stenosis (AS) is a prevalent valvular heart disease, particularly in developing countries, and its incidence increases with an aging population,1,2 affecting 2–9% of older persons.2–4 Echocardiography serves as the cornerstone of evaluating and grading AS. Aortic stenosis severity is generally determined based on aortic valve area (AVA) and mean pressure gradient (MPG). Discordant echocardiographic measurements are occasionally encountered; some patients may have severe stenosis based on the AVA but not severe stenosis based on MPG, even when left ventricular ejection fraction (LVEF) is preserved.5
Previous studies have indicated that patients with low-flow, low-gradient, severe AS represent a subgroup with advanced-stage AS, reduced stroke volume (SV), and poor prognoses.6–9 Conversely, another study indicated that the prognoses of these patients were similar to those of patients with moderate AS.10 Symptomatic patients with paradoxical low-flow low-gradient (PLFLG) severe AS have been reported to have poor prognoses in many studies, and guidelines recommend invasive therapy for stage D valvular heart disease.11 However, this inconsistency between MPG and AVA is common in daily clinical practice, making proper classification of AS severity challenging. Therefore, the prognostic implications of low-gradient severe AS remain controversial and are not fully understood, and most previous studies have relied on echocardiographic measurements performed at rest.
Exercise testing has demonstrated the utility of identifying symptoms or abnormal haemodynamic responses during exercise in patients with asymptomatic AS. Exercise stress echocardiography (ESE) provides additional information on the flow and pressure dynamics associated with AS. However, limited evidence supports ESE as a valuable tool for evaluating asymptomatic AS. Previous studies have reported that increased MPG levels during exercise and exercise-induced pulmonary hypertension (EIPH) were important indicators of symptom development and adverse outcomes.12,13 However, other studies have questioned the efficacy of these findings in risk stratification, possibly because they are influenced by contractile reserves and myocardial responses.14 Therefore, this study aimed to elucidate the prognoses of asymptomatic patients with low-gradient severe AS in comparison with those with moderate AS and explore additional information ESE can offer for risk stratification in this cohort.
Methods
Study design
This study retrospectively observed 143 consecutive asymptomatic patients with either moderate- (MPG < 40 mmHg and AVA 1.0–1.5 cm2) or low-gradient severe (MPG < 40 mmHg and AVA < 1.0 cm2) AS and preserved LVEF (≥50%), who underwent ESE between January 2013 and December 2021 at St Marianna University Hospital. All patients in this study are at least 20 years old. The study protocol was approved by the ethics committee of St Marianna University School of Medicine (No. 6250), and the need for informed consent was waived due to the retrospective nature of the study.
Resting echocardiography
All patients underwent comprehensive two-dimensional and Doppler transthoracic echocardiography before exercise testing in accordance with the American Society of Echocardiography guidelines.15 An experienced sonographer performed all echocardiographic procedures using Vivid E9 or E95 ultrasound systems (General Electric Healthcare, Little Chalfont, UK). The left ventricular (LV) end-diastolic volume (EDV) and end-systolic volume (ESV) were measured using the Simpson biplane method. The LVEF was calculated as follows: [(EDV − ESV)/EDV] × 100. Continuous-wave Doppler was used to measure the maximal aortic valve velocities in apical three- or five-chamber views, and the peak and mean gradients were estimated based on the simplified Bernoulli equation. The LV outflow tract (LVOT) diameter was measured using zoomed parasternal long-axis views. The LVOT velocities acquired using pulsed-wave Doppler and the velocity–time integrals (VTI LVOT) were measured.
The SV was calculated using the following formula: (LVOT diameter/2)2 × 3.14 × VTI LVOT. Subsequently, the SV index (SVi) and cardiac output (CO) were estimated using the following formulas: SVi = SV/body surface area (BSA) and CO = SV × heart rate (HR). The AVA was calculated using the continuity equation, and the AVA index was calculated by dividing it with the BSA. The global LV afterload was estimated using the valvulo-arterial impedance (Zva), formulated as follows: Zva = (systolic blood pressure + MPG)/SVi.16 The systolic pulmonary artery pressure (SPAP) was derived from the regurgitant jet of tricuspid regurgitation (TRPG), adding the estimated right atrial pressure from the inferior vena cava (IVC). The tricuspid annulus plane systolic excursion (TAPSE) was assessed using the M-mode on the tricuspid annulus and expressed as the longitudinal systolic function of shortening the right ventricle. The e′ was measured from the apical four-chamber view, with a 2–5 mm sample volume placed at the septal corner of the mitral annulus. Absolute values of echocardiographic measurements during exercise stress were used and not the change from rest. To avoid difficulties in measuring E and A waves during exercise, data before fusion at an HR of around 100 b.p.m. were adopted. In atrial fibrillation cases, data obtained at a relatively constant RR interval were used.
Exercise stress echocardiography
Following comprehensive transthoracic echocardiography at rest, the patients underwent a symptom-limited graded exercise test in a semi-supine position on a bicycle ergometer table tilted to 20°, as previously described.17 After maintaining an initial workload of 10 W for 3 min, the workload was increased by 10 W every 3 min. A single-lead electrocardiogram was continuously monitored, and blood pressure was measured at rest and every 1 min during exercise. Patients were excluded if they had the following abnormalities: (i) occurrence of angina, dizziness, or syncope; (ii) a decrease in systolic blood pressure (SBP) below baseline and (iii) complex arrhythmia during exercise.
Endpoint
Follow-up data were collected from the medical records. The primary endpoint of the present study was the occurrence time of the first composite endpoint, defined as cardiovascular death, aortic valve replacement due to AS-related symptoms (syncope, dyspnoea, and angina), and hospitalization for heart failure.
Statistical analysis
Continuous variables are expressed as mean values with standard deviations, or median values with interquartile ranges (IQR). Categorical variables are expressed as numbers and percentages. Student’s t-test was used to analyse continuous variables with normal distributions, and the Mann–Whitney U-test was used to analyse continuous variables with non-normal distributions. Categorical variables were compared using Fisher’s exact or χ2 tests, as appropriate.
Statistical significance was set at P < 0.05. The cumulative probability of event-free survival was estimated using the Kaplan–Meier method and was compared between groups using a log-rank test. The optimal cut-off value of E/e′ during exercise was determined based on the receiver operating characteristics curve and the highest Youden index. Univariable and multivariable Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals for clinical outcomes. Data analyses were performed using JMP 16 (SAS Institute Japan, Inc., Tokyo, Japan) and R statistical software (version 4.2.2; R Foundation for Statistical Computing, Vienna, Austria).
Results
A total of 21 patients were excluded due to the following reasons: (i) abnormal exercise response (n = 4; atrial fibrillation tachycardia, advanced atrioventricular block during exercise, ventricular tachycardia, and ST change) and (ii) early intervention [n = 17; transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) within 90 days after ESE]. The remaining 122 patients, who were managed conservatively, were included in this study (Figure 1).
Figure 1.
Flow chart showing study participant distribution.
Baseline characteristics
Table 1 shows the baseline characteristics of the study cohort. A total of 59 (48.3%) patients were male, and the median age was 76.5 (IQR: 71.0–80.3) years. No significant differences in sex, age, comorbidities, or medications were observed between patients with moderate AS and those with low-gradient severe AS. However, patients with low-gradient severe AS had significantly smaller BSAs.
Table 1.
Baseline clinical characteristics of the population
| All (n = 122) | Moderate AS (n = 59) | LG severe AS (n = 63) | P-value | |
|---|---|---|---|---|
| Sex, male | 59 (48.3) | 33 (55.9) | 26 (41.3) | 0.105 |
| Age, years | 76.5 (71.0–80.3) | 76.0 (72.0–81.0) | 77.0 (70.0–80.0) | 0.912 |
| Body surface area, m2 | 1.55 (1.42–1.71) | 1.60 (1.50–1.80) | 1.49 (1.39–1.63) | <0.001 |
| Hypertension | 80 (65.6) | 41 (69.5) | 39 (61.9) | 0.378 |
| Diabetes mellitus | 24 (19.7) | 9 (15.3) | 15 (23.8) | 0.235 |
| Dyslipidaemia | 52 (42.6) | 27 (45.8) | 25 (39.7) | 0.497 |
| CAD | 24 (19.7) | 12 (20.3) | 12 (19.1) | 0.858 |
| Haemodialysis | 5 (4.1) | 2 (3.4) | 3 (4.8) | 0.703 |
| Atrial fibrillation | 29 (23.8) | 16 (27.1) | 13 (20.6) | 0.401 |
| β-Blocker | 24 (19.7) | 15 (25.4) | 9 (14.3) | 0.122 |
| ACE inhibitor/ARB | 48 (39.3) | 24 (40.7) | 24 (38.1) | 0.770 |
| MRA | 4 (3.3) | 2 (3.4) | 2 (3.2) | 0.947 |
| Diuretics | 10 (8.2) | 6 (10.2) | 4 (6.4) | 0.442 |
| Bicuspid | 12 (9.9) | 6 (10.2) | 6 (9.5) | 0.905 |
Data are mean ± SD, median (IQR), or n (%).
LG, low gradient; CAD, coronary artery disease; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor; MRA, mineralocorticoid receptor antagonist.
Resting and exercise echocardiography
The ESE data are summarized in Tables 2 and 3. No significant differences in SBP or HR were observed between the two groups at rest. However, patients with low-gradient severe AS had significantly lower AVA and AVA indices, higher MPG, and smaller left ventricular end-diastolic volume and left ventricular end-systolic volume than those with moderate AS. The LVEF was similar in both groups. SV and CO were significantly smaller in patients with low-gradient severe AS, possibly because of the LV size. The percentage of low-flow status was significantly higher in patients with low-gradient severe AS. The two groups had no significant differences in diastolic function, right ventricular function, or SPAP. SBP during exercise was comparable between the two groups. However, patients with low-gradient severe AS had significantly higher HR than those with moderate AS. Patients with severe mitral regurgitation were not included in this study.
Table 2.
Comparison of resting echocardiographic data between patients with moderate- and low-gradient severe aortic stenosis
| All (n = 122) | Moderate AS (n = 59) | LG severe AS (n = 63) | P-value | |
|---|---|---|---|---|
| SBP, mmHg | 140.1 (±21.2) | 141.5 (±20.9) | 138.9 (±21.5) | 0.507 |
| HR, b.p.m. | 69.0 (62.0–77.9) | 66.0 (62.0–73.0) | 71.0 (62.0–82.0) | 0.051 |
| AVA, cm2 | 1.01 (±0.23) | 1.20 (±0.14) | 0.83 (±0.12) | <0.001 |
| AVA index, cm2/m2 | 0.64 (±0.15) | 0.74 (±0.13) | 0.55 (±0.09) | <0.001 |
| MPG, mmHg | 20.5 (15.6–26.4) | 16.2 (13.4–22.1) | 24.4 (20.0–29.4) | <0.001 |
| LVDd, mm | 43.6 (±5.6) | 44.6 (±6.0) | 42.7 (±5.0) | 0.051 |
| LVDs, mm | 26.0 (24.0–29.3) | 27.0 (25.0–31.0) | 26.0 (24.0–29.0) | 0.058 |
| LV mass index, g/m2 | 81.8 (73.1–98.3) | 80.3 (71.1–97.3) | 82.1 (73.9–98.5) | 0.869 |
| SV, mL | 65.3 (58.0–74.1) | 69.0 (61.0–81.1) | 62.7 (54.0–72.0) | <0.001 |
| SV index, mL/m2 | 42.5 (36.5–47.3) | 43.4 (38.8–47.3) | 41.5 (34.7–47.1) | 0.084 |
| Low flow, % | 22 (18.0) | 6 (10.2) | 16 (25.4) | 0.026 |
| CO, L/min | 4.6 (3.9–5.3) | 4.9 (4.1–5.7) | 4.2 (3.7–5.1) | 0.027 |
| LVEDV, mL | 81.0 (67.6–99.0) | 85.0 (73.0–103.9) | 77.7 (67.0–94.0) | 0.053 |
| LVESV, mL | 26.7 (22.0–34.0) | 30.0 (22.5–39.5) | 25.0 (21.0–31.4) | 0.035 |
| LVEF, % | 66.1 (±6.0) | 65.3 (±6.7) | 66.7 (±5.2) | 0.208 |
| LAV index, mL/m2 | 37.5 (30.0–45.8) | 37.4 (31.6–45.8) | 37.6 (28.7–45.8) | 0.877 |
| E, cm/s | 73.0 (59.5–95.0) | 74.0 (58.0–94.0) | 69.0 (60.0–98.0) | 0.890 |
| e′, cm/s | 5.1 (4.3–6.1) | 5.3 (4.5–6.1) | 4.8 (4.1–6.0) | 0.171 |
| E/e′ | 13.7 (11.1–19.6) | 13.4 (11.0–19.5) | 14.8 (11.3–19.8) | 0.358 |
| E/A | 0.74 (0.63–0.86) | 0.78 (0.66–0.89) | 0.73 (0.61–0.85) | 0.715 |
| Abnormal, % | 78 (84.8) | 36 (85.7) | 42 (84.0) | |
| Pseudonormal, % | 14 (15.2) | 6 (14.3) | 8 (16.0) | |
| ZVa, mmHg/mL/m2 | 3.78 (3.30–4.44) | 3.68 (3.00–4.18) | 4.12 (3.48–4.50) | 0.010 |
| MR ≥ 3° | 1 (0.8) | 0 (0) | 1 (1.6) | 0.331 |
| TRPG, mmHg | 23.0 (19.9–27.0) | 22.3 (18.9–27.5) | 23.5 (20.3–27.0) | 0.828 |
| SPAP, mmHg | 26.0 (22.9–30.1) | 25.3 (21.9–30.5) | 26.5 (23.3–30.0) | 0.838 |
| TAPSE, mm | 19.8 (16.9–22.1) | 19.9 (17.7–23.0) | 19.3 (16.7–21.5) | 0.484 |
Data are mean ± SD, median (IQR), or n (%).
SBP, systolic blood pressure; LVDd, left ventricular diastolic dimension; LVDs, left ventricular systolic dimension; LAV, left atrial volume.
Table 3.
Comparison of exercise echocardiographic data between the patients with moderate- and low-gradient severe aortic stenosis
| All (n = 122) | Moderate AS (n = 59) | LG severe AS (n = 63) | P-value | |
|---|---|---|---|---|
| Exercise intensity, METs | 3.5 (3.0–4.4) | 3.5 (2.9–4.3) | 3.7 (3.1–4.6) | 0.357 |
| Peak workload, W | 40 (30–57.5) | 40 (30–60) | 40 (30–50) | 0.200 |
| SBP, mmHg | 175.2 (±30.5) | 172.7 (±28.1) | 177.4 (±32.5) | 0.409 |
| HR, b.p.m. | 110.3 (±21.2) | 105.6 (±20.8) | 114.4 (±20.9) | 0.024 |
| AVA, cm2 | 1.04 (0.92–1.25) | 1.24 (1.14–1.41) | 0.92 (0.79–1.02) | <0.001 |
| AVA index, cm2/m2 | 0.66 (0.58–0.80) | 0.77 (0.64–0.92) | 0.59 (0.49–0.68) | <0.001 |
| MPG, mmHg | 26.4 (18.8–35.2) | 20.0 (16.6–27.8) | 31.6 (25.3–38.5) | <0.001 |
| SV, mL | 71.0 (61.3–83.2) | 74.2 (68.9–88.9) | 64.6 (55.4–78.0) | <0.001 |
| SV index, mL/m2 | 46.3 (±10.6) | 49.0 (±10.9) | 43.8 (±9.8) | 0.006 |
| CO, L/min | 7.8 (±1.9) | 8.2 (±1.8) | 7.5 (±1.8) | 0.042 |
| LVEDV, mL | 86.0 (73.0–107.5) | 90.0 (74.0–109.7) | 81.4 (66.6–104.4) | 0.079 |
| LVESV, mL | 24.0 (18.0–30.9) | 25.0 (19.7–32.9) | 22.7 (17.0–28.9) | 0.330 |
| LVEF, % | 73.0 (68.5–76.0) | 73.0 (67.0–76.0) | 73.6 (69.0–75.9) | 0.635 |
| E, cm/s | 127.0 (107.8–151.0) | 125.0 (103.0–149.0) | 131.0 (112.0–161.0) | 0.133 |
| e′, cm/s | 8.1 (6.9–10.3) | 8.0 (6.7–9.1) | 8.3 (6.9–12.5) | 0.011 |
| E/e′ | 15.3 (11.8–18.8) | 14.9 (12.7–19.3) | 15.3 (10.3–18.0) | 0.816 |
| E/A | 1.04 (0.85–1.23) | 1.05 (0.83–1.24) | 0.97 (0.85–1.22) | 0.841 |
| Abnormal relaxation, % | 46 (50.6) | 18 (43.9) | 28 (56.0) | |
| Pseudonormal, % | 45 (49.5) | 23 (56.1) | 22 (44.0) | |
| ZVa, mmHg/mL/m2 | 4.48 (3.71–5.27) | 3.96 (3.29–4.91) | 4.95 (4.09–5.71) | <0.001 |
| TRPG, mmHg | 45.4 (±11.6) | 44.1 (±12.7) | 46.5 (±10.5) | 0.262 |
| SPAP, mmHg | 55.4 (±11.6) | 54.1 (±12.7) | 56.5 (±10.5) | 0.262 |
| Exercise-induced PH, % | 45 (38.5) | 22 (39.3) | 23 (37.7) | 0.861 |
| TAPSE, mm | 24.0 (±5.5) | 24.4 (±5.6) | 23.6 (±5.3) | 0.421 |
Data are mean ± SD, median (IQR), or n (%).
MET, metabolic equivalent.
Aortic stenosis severity parameters during exercise, including AVA and AVA index, were significantly lower, and the MPG was higher in patients with low-gradient severe AS, consistent with the resting data. The LV size during exercise was not significantly different between the two groups; however, patients with low-gradient severe AS had significantly smaller SV and CO during exercise.
Comparisons between outcomes in low-gradient severe aortic stenosis vs. moderate aortic stenosis
During a median follow-up period of 989 (IQR: 578–1571) days, the composite endpoint occurred in 64 patients (cardiovascular death, n = 2; hospitalization for heart failure, n = 2; and AVR, n = 58). The Kaplan–Meier analysis revealed a significantly lower event-free survival rate in patients with low-gradient severe AS than in those with moderate AS (log-rank test, P < 0.001; Figure 2). Multivariable Cox regression analysis revealed that low-gradient severe AS was independently associated with the event risk (hazard ratio = 2.386, P = 0.009 and P = 0.002; Table 4).
Figure 2.
Event-free survival curve of moderate aortic stenosis vs. low-gradient severe aortic stenosis.
Table 4.
Univariable and multivariable Cox regression analyses for predicting aortic valve-related events in patients with moderate and low-gradient severe aortic stenosis
| Univariable model | Multivariable model | |||
|---|---|---|---|---|
| Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value | |
| Age, years | 1.032 (1.002–1.063) | 0.039 | 1.038 (1.007–1.071) | 0.018 |
| SBP, mmHg | 0.998 (0.986–1.010) | 0.715 | 0.994 (0.981–1.007) | 0.386 |
| Sex, male | 1.077 (0.655–1.770) | 0.771 | 1.052 (0.592–1.867) | 0.863 |
| HR, b.p.m. | 1.018 (0.999–1.038) | 0.064 | 1.010 (0.988–1.032) | 0.398 |
| Low-gradient severe AS | 2.344 (1.397–3.933) | 0.001 | 2.386 (1.367–4.166) | 0.002 |
Univariable and multivariable Cox regression analyses
The prognostic factors in patients with low-gradient severe AS were investigated. The cut-off value for the mitral E/e′ index during exercise was set at 15.4 (receiver operating characteristic curve, P = 0.007; area under the curve (AUC), 0.749; sensitivity, 65.9%; specificity, 86.3%). The high mitral E/e′ index during exercise (≥15.4) was significantly associated with an increased risk of adverse events in the univariable analysis, in patients with low-gradient severe AS (P = 0.011; Table 5). Contrastingly, the SPAP at rest and during exercise, and low-flow status were not associated with the event risk.
Table 5.
Univariable and multivariable Cox regression analyses for predicting aortic valve-related events in patients with low-gradient severe aortic stenosis
| Univariable model | Age-, sex-, and BSA-adjusted model | Model 1 | Model 2 | |||||
|---|---|---|---|---|---|---|---|---|
| Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value | |
| AVA at rest, cm2 | 0.277 (0.033–2.996) | 0.262 | 0.041 (0.003–0.638) | 0.021 | 0.037 (0.002–0.623) | 0.021 | ||
| MPG at rest, mmHg | 1.022 (0.973–1.072) | 0.377 | 1.025 (0.976–1.074) | 0.304 | 1.023 (0.975–1.072) | 0.340 | ||
| E/e′ at rest (continuous) | 1.034 (0.987–1.078) | 0.136 | 1.003 (0.984–1.076) | 0.193 | ||||
| Low flow at rest | 1.065 (0.528–2.148) | 0.860 | ||||||
| SPAP at rest, mmHg | 1.040 (0.981–1.102) | 0.182 | ||||||
| ZVa at rest, mmHg/mL/m2 | 1.018 (0.789–1.296) | 0.891 | ||||||
| AVA during exercise, cm2 | 0.624 (0.141–2.863) | 0.541 | 0.394 (0.066–2.221) | 0.299 | ||||
| MPG during exercise, mmHg | 1.004 (0.984–1.022) | 0.657 | 1.001 (0.980–1.020) | 0.885 | ||||
| E/e′ during exercise | 1.060 (1.026–1.091) | <0.001 | 1.065 (1.028–1.099) | <0.001 | 1.075 (1.035–1.113) | <0.001 | 1.066 (1.031–1.102) | <0.001 |
| High E/e′ during exercise | 2.312 (1.209–4.419) | 0.011 | 2.340 (1.187–4.614) | 0.014 | 2.337 (1.187–4.600) | 0.014 | 2.350 (1.192–4.635) | 0.014 |
| SPAP during exercise, mmHg | 1.040 (0.981–1.102) | 0.182 | ||||||
| ZVa during exercise | 0.863 (0.680–1.064) | 0.195 | ||||||
| mmHg/mL/m2 | ||||||||
Model 1 was adjusted for age, sex, BSA, AVA at rest, and the high E/e′ ratio during exercise.
Model 2 was adjusted for age, sex, BSA, MPG at rest, and the high E/e′ ratio during exercise.
BSA, body surface area; CI, confidence interval.
After adjusting for age, sex, and BSA, the AVA at rest and the high mitral E/e′ during exercise were significantly associated with an increased risk of adverse events. The variables for the multivariable Cox regression analysis were selected (Model 1: age, sex, BSA, AVA at rest, and the high mitral E/e′ index during exercise; Model 2: age, sex, BSA, MPG at rest, and the high mitral E/e′ index during exercise). Multivariable Cox regression analysis revealed that the AVA at rest and the high mitral E/e′ index during exercise were independently associated with the event risk (hazard ratio = 0.024 and 2.350, P = 0.009 and P = 0.014, respectively; Table 5). E/e′ during exercise was also significantly associated with adverse events in flow-specific analyses [low-flow: HR 1.075 (1.012–1.142); normal-flow: HR 1.056 (1.012–1.093); both P < 0.05].
Outcomes associated with the high mitral E/e′ index during exercise in patients with low-gradient severe aortic stenosis
The patients in this study were divided into two groups based on their mitral E/e′ during exercise as follows: low E/e′ (<15.4, n = 33) and high E/e′ (≥15.4, n = 30) groups. Table 6 summarizes the ESE data. No significant differences in sex, age, BSA, and the percentage of low-flow status and MR (≥3°) were observed between patients in the low and high E/e′ groups. The high E/e′ group had a significantly larger left atrial size, lower LVEF at rest, and lower AVA and AVA index during exercise than the low E/e′ group. Kaplan–Meier analysis indicated that the high E/e′ group had a significantly lower event-free survival rate than the low E/e′ group (log-rank test, P = 0.009; Figure 3). Prognostic stratification according to the mitral E/e′ index during exercise was possible in patients with low-gradient severe AS. Kaplan–Meier analysis stratified according to reduced (≤35 mL/m2, n = 47) and preserved (>35 mL/m2, n = 16) SVi showed no statistically significant difference in the rate of event-free survival (log-rank, P = 0.860; Figure 4).
Table 6.
Comparison of resting and exercise echocardiographic findings between the low and high E/e′ during exercise in patients with low-gradient severe AS
| Low E/e′ (n = 33) | High E/e′ (n = 30) | P-value | |
|---|---|---|---|
| Sex, male | 13 (39.4) | 13 (43.3) | 0.751 |
| Age, years | 77.0 (69.5–82.0) | 77.5 (72.5–80.0) | 0.673 |
| Body surface area, m2 | 1.48 (1.39–1.61) | 1.51 (1.38–1.70) | 0.693 |
| Exercise intensity, METs | 3.5 (3.1–4.9) | 3.7 (3.1–4.4) | 0.566 |
| Peak workload, M | 40.0 (30.0–55.0) | 46.5 (37.5–50.0) | 0.516 |
| At rest | |||
| SBP, mmHg | 142.9 (±23.0) | 134.6 (±19.3) | 0.133 |
| HR, b.p.m. | 71.0 (63.0–85.8) | 72.0 (58.0–82.0) | 0.600 |
| AVA, cm2 | 0.84 (±0.11) | 0.81 (±0.13) | 0.262 |
| AVA index, cm2/m2 | 0.56 (±0.09) | 0.53 (±0.09) | 0.172 |
| MPG, mmHg | 23.2 (19.3–29.8) | 24.6 (20.8–28.8) | 0.752 |
| LV mass index, g/m2 | 80.2 (73.7–95.5) | 84.5 (74.7–107.9) | 0.417 |
| LVEDV, mL | 77.7 (67.3–94.8) | 77.0 (63.3–92.7) | 0.863 |
| LVESV, mL | 25.0 (21.1–30.8) | 25.3 (20.3–31.7) | 0.287 |
| LAV index, mL/m2 | 34.3 (26.7–43.3) | 41.6 (31.1–52.6) | 0.011 |
| SV, mL | 62.7 (57.1–72.4) | 61.6 (49.8–71.3) | 0.444 |
| SVi, mL/m2 | 41.7 (35.5–48.4) | 41.3 (32.6–45.7) | 0.325 |
| Low flow, % | 6 (20.0) | 10 (30.3) | 0.348 |
| CO, L/min | 4.5 (3.8–5.3) | 4.1 (3.7–4.9) | 0.204 |
| LVEF, % | 68.1 (±4.6) | 65.2 (±5.4) | 0.028 |
| E, cm/s | 65.0 (57.0–80.0) | 88.5 (63.0–114.8) | <0.001 |
| e′, cm/s | 4.8 (4.3–6.2) | 4.6 (3.9–5.9) | 0.261 |
| E/e′ | 12.9 (9.6–15.4) | 19.6 (13.6–22.4) | <0.001 |
| E/A | 0.66 (0.58–0.85) | 0.75 (0.61–0.87) | 0.203 |
| Abnormal, % | 24 (85.7) | 18 (81.8) | |
| Pseudonormal, % | 4 (14.3) | 4 (18.2) | |
| MR ≥ 3° | 0 | 1 (3.3) | 0.290 |
| SPAP, mmHg | 25.3 (23.1–28.4) | 27.9 (23.9–32.1) | 0.085 |
| TAPSE, mm | 19.8 (17.0–21.6) | 18.9 (16.0–21.4) | 0.243 |
| During exercise | |||
| SBP, mmHg | 186.7 (±29.9) | 166.9 (±32.7) | 0.016 |
| HR, b.p.m. | 117.0 (±23.1) | 111.5 (±18.0) | 0.294 |
| AVA, cm2 | 0.96 (0.83–1.03) | 0.86 (0.69–0.99) | 0.050 |
| AVA index, cm2/m2 | 0.63 (0.54–0.70) | 0.57 (0.48–0.64) | 0.025 |
| MPG, mmHg | 31.6 (24.8–38.4) | 31.9 (25.9–42.1) | 0.456 |
| SV, mL | 64.0 (57.5–80.1) | 65.7 (53.6–76.2) | 0.200 |
| SVi, mL/m2 | 45.7 (±10.0) | 41.7 (±9.3) | 0.109 |
| CO, L/min | 7.9 (±1.7) | 7.1 (±1.9) | 0.079 |
| LVEF, % | 74.0 (69.9–76.8) | 72.4 (67.0–75.4) | 0.354 |
| E, cm/s | 126.0 (104.0–141.5) | 140.0 (122.5–175.8) | 0.004 |
| e′, cm/s | 11.9 (7.8–14.2) | 7.3 (6.3–8.4) | <0.001 |
| E/e′ | 10.7 (9.2–13.6) | 18.2 (16.6–23.0) | <0.001 |
| E/A | 0.93 (0.77–1.05) | 1.16 (0.92–1.50) | 0.004 |
| Abnormal, % | 21 (75.0) | 7 (31.8) | |
| Pseudonormal, % | 7 (25.0) | 15 (68.2) | |
| SPAP, mmHg | 55.8 (±10.7) | 57.3 (±10.5) | 0.599 |
| TAPSE, mm | 25.1 (21.4–27.0) | 24.3 (18.4–26.3) | 0.052 |
Data are mean ± SD, median (IQR), or n (%).
Figure 3.
Event-free survival curve according to mitral E/e′ in patients with low-gradient severe AS.
Figure 4.
Event-free survival curve of reduced vs. preserved stroke volume index in patients. PLFLG, paradoxical low-flow low gradient; NFLG, normal-flow low gradient.
Discussion
The main findings of this study are as follows: (i) asymptomatic patients with low-gradient severe AS had worse prognoses than those with moderate AS with only a 40% event-free survival rate and (ii) an increase in the mitral E/e′ index during exercise was effective for stratifying prognosis in asymptomatic patients with low-gradient severe AS.
Prognosis of low-gradient severe aortic stenosis
Previous studies have suggested that low-gradient severe AS might be caused by a reduced SV assessed using Doppler echocardiography, signifying an advanced stage of severe AS, compromised impaired ventricular function, and poor prognosis requiring early valve intervention.11,18 However, Jander et al.10 suggested that outcomes and progression rates in patients with low-gradient severe AS were comparable to those in patients with moderate AS. Contrastingly, the present study’s findings show worse prognoses in asymptomatic patients with low-gradient severe AS, potentially due to the inclusion of older and smaller patients with smaller LVs when compared with the study by Jander et al. Several mechanisms could account for the low gradient in severe AS despite preserved LVEF. One possible mechanism could be reduced SV even with preserved LVEF, due to concentric LV hypertrophy or impaired longitudinal LV myocardial function.
Nonetheless, lower transvalvular pressure gradients may still occur in patients with small body sizes and LV dimensions. There could be several reasons for the low gradient, even though there was a severely stenotic AVA in the presence of preserved ejection fraction (EF). One possible reason is the outcome of reduced SV, even though EF is preserved, due to decreased ventricular size and/or impaired myocardial function.7,19 However, even when the SV is normal, patients with smaller body sizes and LV dimensions may still show a lower transvalvular pressure gradient.10
Exercise stress echocardiography for low-gradient severe aortic stenosis
Risk stratification of patients with asymptomatic AS remains controversial. Exercise stress echocardiography has emerged as an attractive risk-stratification tool for distinguishing asymptomatic patients with AS. An increase in MPG > 18–20 mmHg and an increase in SPAP > 60 mmHg during exercise have been suggested prognostic markers.12,13 However, the evidence remains limited, and Goublaire et al.14 reported that these parameters are ineffective for prognostic stratification. Furthermore, studies using stress echocardiography in patients with low-gradient severe AS are limited. Clavel et al. investigated the prognostic value of exercise and dobutamine stress echocardiography (DSE) in patients with severe PLFLG AS. They reported that prognostic stratification of patients with PLFLG severe AS was difficult using resting echocardiographic parameters, but projected AVA was effective for prognostic stratification.20 This study examined asymptomatic patients with ESE and symptomatic patients with DSE but did not discuss any parameters that reflect haemodynamics during exercise. It is the first study to examine ESE in patients with asymptomatic low-gradient severe AS, including echocardiographic index haemodynamics during exercise. Haemodynamic changes during exercise in patients with symptomatic, paradoxical, low-gradient severe AS have been previously studied using cardiopulmonary exercise testing combined with right heart catheterization and Doppler echocardiographic measurements. Peak oxygen consumption correlated inversely with the rate of pulmonary capillary wedge pressure (PCWP) increase. The ability to reduce vascular and valvular loads determines the effect of exercise on the PCWP. Baseline haemodynamic parameters did not predict the response to PCWP. Additionally, the haemodynamic responses did not show significant differences between patients with low flow (SVi ≤ 35 mL/m2) and those with the normal flow (SVi > 35 mL/m2).21
The current study investigated the relationship between prognosis and ESE parameters. MPG and EIPH,12,13 which were previously reported in asymptomatic AS, were difficult to use for prognostic stratification. However, the mitral E/e′ index during exercise was useful for prognostic stratification in patients with low-gradient severe AS. Changes in MPG and EIPH are affected by the SV and HR and may not be good prognostic indicators in low-gradient severe AS with reduced SV. In addition, it is difficult to assess whether a patient has EIPH because the right atrial pressure during exercise is difficult to estimate and is sometimes underestimated.22 The mitral E/e′ index correlates with LV stiffness and fibrosis23,24 and is recognized as one of the indicators of LV diastolic function. In patients with heart failure with preserved ejection fraction (HFpEF), no increase in LV filling pressure was observed at rest; however, there were cases in which there was an increase in LV filling pressure with exercise. During exercise, in patients with HFpEF, impaired early diastolic relaxation, reduced increments in suction, and poor LV compliance result in insufficient increments in SV and CO, leading to increased LV filling pressure and higher PASP.25,26 The mitral E/e′ index correlates with invasively measured LVEDP during exercise.26 Therefore, the mitral E/e′ index during exercise is an important parameter in diagnosing HFpEF.27 In addition, patients with elevated mitral E/e′ index during exercise are at increased risk of death.28 A previous study showed that patients with symptomatic PLFLG with severe AS had a more advanced stage of diastolic dysfunction and significantly worse prognoses than those with asymptomatic PLFLG with severe AS.7,9 These results suggested a possible link between severe AS and HFpEF in some patients.29 Based on the results of the present study, patients with asymptomatic low-gradient severe AS who exhibited an increase in E/e′ during exercise, which is associated with HFpEF, were observed to have poorer prognoses.
Limitations
This study had several limitations. First, this was a single-centre, retrospective observational study, although long-term follow-up was available. Therefore, inherent bias cannot be excluded in this study type. Although the sample size was comparable to that of previous studies, it was relatively small, with a limited number of composite events. To date, no multicentre studies have been conducted on ESE in patients with low-gradient severe AS. Therefore, these results should be validated in multicentre prospective studies with larger populations. Second, the study population consisted of asymptomatic patients with moderate- or low-gradient severe AS, who could undergo exercise testing. This study does not reflect low-gradient AS as a whole because it excluded patients who underwent SAVR or TAVR within 90 days of ESE and included asymptomatic patients. However, the results may reflect actual clinical practice since ESE is contraindicated in patients with symptomatic severe AS.30 Third, patients with abnormal exercise test findings and early intervention were excluded, and only those who were followed up with conservative treatment were included. Therefore, the study did not reflect the overall prognoses of patients with low-grade severe AS. Fourth, most of the events in this study were AVR, although cases with AVR within 90 days of ESE were excluded. Most of the patients who underwent AVR had symptom onset and the indication was also determined by the heart-valve team. Waiting until heart failure hospitalization for AVR would be difficult in clinical practice, given the impact on patient outcomes. Fourth, this study examined both the low-flow and normal-flow groups, and there was no difference in prognosis between these groups. There are several reasons for this; for example, asymptomatic patients were entered during outpatient consultation, Japanese patients with AS are more likely to have a sigmoid-shaped septum and the Doppler SV may have been overestimated,31,32 Some patients were diagnosed as asymptomatic in the outpatient setting but were symptomatic in the exercise stress test, and flow statuses may have changed during follow-up.33 Fifth, although only 1 of 122 patients in the present cohort had mitral regurgitation of >3°, care should be taken in the interpretation of E/e′ and exercise stress echocardiography when significant mitral regurgitation is present. Sixth, we obtained e′ at the septal mitral annulus only as in a previous study. It is difficult to measure e′ at the septal and lateral mitral annulus within a limited time during exercise and correct alignment of Doppler angle tends to be difficult during exercise when measuring e′ at the lateral mitral annulus. Seventh, some patients with moderate AS who underwent ESE had ambiguous symptoms. Therefore, selection bias may not be eliminated in the comparison of moderate AS to low-gradient severe AS. Last, the calcium score calculated by CT, which is useful for diagnosing the severity of low-gradient AS with preserved EF, was not measured in this study. Therefore, it is not possible to verify severity in low-gradient AS.
Conclusion
This study suggests that patients with low-gradient severe AS have worse prognoses than those with moderate AS. The mitral E/e′ ratio during exercise is a useful parameter for risk stratification of patients with low-gradient severe AS. Left ventricular diastolic function during exercise may play a crucial role in decision-making for patients with low-gradient severe AS.
Contributor Information
Daisuke Miyahara, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Masaki Izumo, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Yukio Sato, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Tatsuro Shoji, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Risako Murata, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Ryutaro Oda, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Taishi Okuno, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Shingo Kuwata, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Yoshihiro J Akashi, Department of Cardiology, St Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan.
Lead author biography
Daisuke Miyahara is a cardiologist at St Marianna University School of Medicine in Kawasaki, Japan. His research interests include exercise stress echocardiography, structured heart disease, chronic heart failure, and cardiomyopathies.
Data availability
The data underlying this article were provided by St Marianna University Hospital. Data will be shared on request to the corresponding author with the permission of St Marianna University Hospital.
Funding
None.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data underlying this article were provided by St Marianna University Hospital. Data will be shared on request to the corresponding author with the permission of St Marianna University Hospital.