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Abstract

Aims

In patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), data on the differences in subsequent cardiac structure and function among stratified groups with flow gradient patterns through the aortic valve are insufficient.

Methods and results

In this large multicenter study, 4523 patients undergoing TAVI for severe AS between 2013 and 2019 were divided into three groups according to the following criteria: (i) high-gradient AS (HG-AS) [mean pressure gradient (MPG) ≥ 40 mmHg], (ii) classical low-flow low-gradient AS (cLFLG-AS) [MPG < 40 mmHg, left ventricular (LV) ejection fraction (LVEF) <50%], and (iii) paradoxical low-flow low-gradient AS (pLFLG-AS) [MPG < 40 mmHg, LVEF ≥ 50% but stroke volume index (SVi) <35 mL/m2]. Echocardiography was performed at baseline, post-procedure, and 1 year post-TAVI. 3697, 507, and 319 patients had HG-AS, cLFLG-AS, and pLFLG-AS, respectively. After adjusting for clinical factors, cLFLG-AS and pLFLG-AS had an ∼1.5-fold higher 2-year all-cause mortality compared with HG-AS. During 1 year following TAVI, compared with HG-AS, cLFLG-AS showed greater reduction of LV systolic diameter (LVDs) and LV diastolic diameter (LVDd) and greater increase of LVEF (P < 0.001 for all), and changes in LV mass index (LVMi) and SVi were comparable (P = 0.915 and P = 0.821, respectively). However, pLFLG-AS demonstrated less reduction of LVDs and LVDd (P = 0.039 and P = 0.001, respectively), less improvement of LVEF and LVMi (P = 0.045 and P < 0.001, respectively), and comparable change in SVi (P = 0.364).

Conclusion

During 1 year post-TAVI, compared with HG-AS, cLFLG-AS achieves smaller LV diameters, greater increase in LVEF, and comparable regression of LVMi, whereas pLFLG-AS does not.

Graphical Abstract
Graphical Abstract
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aortic stenosis, low-flow low-gradient aortic stenosis, transcatheter aortic valve implantation, echocardiography

Introduction

Aortic stenosis (AS) is the most common valvular heart disease in elderly patients.1 Transcatheter aortic valve implantation (TAVI) is the standard therapeutic approach for these patients.2 High-gradient AS (HG-AS) is the classical indication for TAVI, whereas one-third of patients with severe AS demonstrate a discordance of echocardiographic grading criteria, where the aortic valve area (AVA) is <1.0 cm2, mean pressure gradient (MPG) is <40 mmHg, and Vmax is <4 m/s. Moreover, some patients who underwent TAVI actually present with low-gradient AS.3–7 In these patients, the diagnosis and management are particularly challenging.8 Patients with low-gradient AS are subdivided into classical low-flow low-gradient (LFLG) AS (cLFLG-AS), when the left ventricular (LV) ejection fraction (LVEF) is <50%, and paradoxical LFLG AS (pLFLG-AS), when the LVEF is normal but the stroke volume index (SVi) is reduced.9 Patients with cLFLG, who are essentially patients with heart failure (HF) with reduced LVEF, often have several relevant comorbidities, such as atrial fibrillation (AF), mitral or tricuspid regurgitation, or coronary artery disease (CAD).5 In contrast, patients with pLFLG-AS are characterized by impaired longitudinal deformation, diastolic dysfunction, and small LV volume, resulting in impaired LV function.9 In this context, previous studies have been published on the clinical outcomes following TAVI in comparison with HG-AS, cLFLG-AS, and pLFLG-AS; however, the results are conflicting.5,7,8,10–13 In addition, data on the difference in subsequent changes in cardiac structure after TAVI in each group stratified based on the flow gradient pattern are insufficient. Therefore, this study, which was based on a multicenter retrospective large registry, aimed to compare the midterm clinical outcomes among three groups, that is, HG-AS, cLFLG-AS, and pLFLG-AS, and to primarily investigate the difference in serial changes of cardiac structures and functions after TAVI using echocardiography.

Methods

Study population and echocardiography assessment

The Optimized CathEter vAlvular iNtervetion Transcatheter Aortic Valve Implantation (OCEAN-TAVI) registry is an ongoing multicenter, observational registry of symptomatic patients with severe AS who underwent TAVI using Edwards Sapien XT, Edwards Sapien 3 (Edwards Lifesciences, Irvine, CA, USA), Medtronic CoreValve, Medtronic Evolut R, or Medtronic Evolut PRO (Medtronic, Minneapolis, MN, USA) prostheses at 14 collaborating high-volume centers in Japan. This registry was designed to record procedural results, post-procedural clinical outcomes, and transitional examination data after TAVI.

Between October 2013 and December 2019, 7391 symptomatic patients who underwent TAVI were prospectively enrolled in the OCEAN-TAVI registry. Of these, we analysed 5560 patients with complete data on LVEF, SVi, and MPG at baseline. Patients were divided into four groups according to their LVEF flow gradient pattern:7,14 (i) HG-AS: MPG ≥ 40 mmHg as stage D1 in the American guidelines; (ii) cLFLG-AS: MPG < 40 mmHg and LVEF < 50% as stage D2; (iii) pLFLG-AS: MPG < 40 mmHg, LVEF ≥ 50%, and SVi < 35 mL/m2 as stage D3; and (iv) normal-flow, low-gradient (NFLG)-AS: MPG < 40 mmHg, LVEF ≥ 50%, and SVi ≥ 35 mL/m2. Subsequently, the NFLG-AS group was excluded from the analysis.

The study protocol was designed in accordance with the 1975 Declaration of Helsinki and approved by the ethics committee of each participating hospital. Written informed consent was obtained from all patients. The authors have full access to the data and are responsible for their integrity. The registry was registered with the University Hospital Medical Information Network (UMIN000020423).

All patients underwent standard 2D B-mode and Doppler transthoracic echocardiography (TTE). All measurements were performed according to the recommendations of the American Society of Echocardiography.15 Based on this protocol, echocardiographic examinations were performed at baseline, during hospitalization after TAVI, and again 1 year after TAVI.

Study endpoint and follow-up

The primary endpoint of this study was the changes in aortic valve hemodynamics and cardiac structure, including indexed AVA (iAVA), MPG, SVi, LVEF, LV systolic diameter (LVDs), LV diastolic diameter (LVDd), left atrial diameter (LAD), left ventricular mass index (LVMi), and relative wall thickness (RWT), evaluated by TTE at baseline, post-procedure, and 1-year follow-up among the HG-AS, cLFLG-AS, and pLFLG-AS groups. The secondary endpoint was the differences in clinical outcomes, including all-cause death, cardiovascular (CV) death, hospitalization for HF (HHF), and composite events with CV death and HHF, during the midterm follow-up after TAVI among the three groups. Among patients who experienced multiple CV events, only the first event was included in the analysis. Procedural outcomes were compared according to the Valve Academic Research Consortium-2 (VARC-2) criteria.16 Paravalvular regurgitation (PVR) was categorized as none/trace, mild, moderate, or severe (three-class grading scheme). The severity of prosthesis–patient mismatch (PPM) was graded using the AVA indexed to body surface area (BSA), with absence of PPM defined as >0.85 cm2/m2, moderate PPM as >0.65 and ≤0.85 cm2/m2, and severe PPM as ≤0.65 cm2/m2. If the patient was obese [body mass index (BMI) ≥30 kg/m2], lower cutoff values of iAVA were used to define moderate (>0.55 and ≤0.70 cm2/m2) and severe (≤0.55 cm2/m2) PPM. Follow-up surveys were conducted at the time of each outpatient visit or by telephone interviews at 30 days, 6 months, and yearly thereafter. Endpoint events were defined according to the VARC-2 criteria.16 Any death due to an unknown cause was defined as a CV-related death.

Statistical analyses

All data were collected from the OCEAN-TAVI registry database. Continuous variables are expressed as means ± standard deviations or medians with interquartile ranges, as appropriate. The Shapiro–Wilk test was used to assess the normality of the data. Categorical variables are expressed as numbers and percentages. Data were compared between groups using Student’s t-test or the Mann–Whitney U test for continuous data. The Wilcoxon rank-sum test was used for within-group comparisons. Categorical variables were analysed using the χ2 or Fisher exact tests. To evaluate differences in clinical outcomes, including all-cause death, CV death, HHF, and composite events of CV death and HHF in cLFLG-AS and pLFLG-AS compared with HG-AS, the Kaplan–Meier method was performed, adjusted by the presumed association with clinical outcomes of main interest as follows: age, sex, BMI, Society of Thoracic Surgeons (STS) mortality score, and New York Heart Association (NYHA) Class III or IV. The results were described using the estimated hazard ratio (HR) and 95% confidence interval (CI). A P-value <0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS statistics version 27 (IBM Corp., Chicago, IL, USA) and EZR version 3.6.0 (Saitama Medical Center, Japan).

Results

Prevalence of the flow gradient patterns and baseline characteristics

Of the 7393 patients included in this analysis, 1833 were excluded because they had no baseline echocardiographic data on SVi, MPG, or LVEF. Moreover, 1037 patients identified with NFLG-AS were excluded from the analysis. We identified 3697 (66.5%) patients with HG-AS, 507 with cLFLG-AS (9.1%), and 319 with pLFLG-AS (5.7%; see Supplementary data online, Figure S1). Compared with HG-AS, cLFLG-AS was characterized by a higher prevalence of younger age (median 84 years vs. 85 years, P < 0.001), male sex (50.3% vs. 28.8%), smaller BMI, larger BSA, worse HF symptom, worse clinical frailty score (CFS), worse renal function, and significantly higher number of diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), and CV disease (CVD), including prior myocardial infarction (MI), prior percutaneous coronary intervention (PCI), prior coronary artery bypass graft (CABG), peripheral artery disease, and AF, leading to a significantly higher STS scores (7.9% vs. 6.0%; Table 1). Regarding echocardiographic parameters, patients with cLFLG-AS had significantly reduced LVEF, enlarged left chambers, lower SVi, and higher LVMi (Table 1). In contrast, compared with HG-AS, pLFLG-AS had more male participants (34.8% vs. 28.8%), larger BSA, worse renal function, and significantly higher numbers of DM, COPD, and CVD as defined above. However, there was no significant difference in the STS score between the groups (6.3% vs. 6.0%; Table 1). Regarding echocardiographic parameters, patients with pLFLG-AS had a significantly higher LVEF, smaller left ventricle, lower SVi, and lower LVMi (Table 1). Supplementary data online, Table S1 summarizes the procedural characteristics and in-hospital outcomes. Compared with HG-AS, cLFLG-AS had a higher prevalence of pre-dilation and urgent or emergent TAVI cases and a longer hospital stay after TAVI (P < 0.001 for all). In contrast, the pLFLG-AS group had a lower prevalence of the transfemoral approach, local anaesthesia, pre- and post-dilation, bicuspid anatomy, and urgent or emergent TAVI compared with HG-AS (P = 0.003, P = 0.041, P < 0.001, P < 0.001, P < 0.001, and P = 0.043, respectively). With respect to in-hospital complications, the cLFLG group had a higher number of ischaemic strokes and fewer new pacemaker implantations (PMIs; P = 0.034 and P = 0.025, respectively), whereas the pLFLG group had a higher number of new PMIs (P = 0.026).

Table 1
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Baseline characteristics and echocardiographic parameters

 OverallHG-AScLFLG-ASpLFLG-ASOverall
Number45233697507319P-value
Age, years85 [81, 88]85 [81, 88]84 [80, 87]*,**85 [82, 88]<0.001
Male, n (%)1431 (31.6)1065 (28.8)255 (50.3)*,**111 (34.8)*<0.001
Body mass index, kg/m222.0 [19.6, 24.5]22.1 [19.6, 24.5]21.2 [19.1, 24.1]*,**22.7 [20.0, 25.0]<0.001
Body surface area, m21.40 [1.30, 1.56]1.40 [1.30, 1.55]1.47 [1.30, 1.60]*1.46 [1.32, 1.58]*<0.001
NYHA functional Class III or IV, n (%)1962 (43.4)1516 (41.0)299 (59.0)*,**147 (46.1)<0.001
Clinical Frail Scale4 [3, 5]4 [3, 4]4 [3, 5]*,**4 [3, 4]<0.001
STS mortality score, %6.2 [4.2, 9.1]6.0 [4.2, 8.8]7.9 [5.0, 12.5]*,**6.3 [4.2, 9.4]<0.001
Past medical history
 Hypertension, n (%)3778 (83.5)3085 (83.4)426 (84.0)267 (83.7)0.944
 Dyslipidemia, n (%)2497 (55.2)2032 (55.0)297 (58.6)168 (52.7)0.196
 Diabetes mellitus, n (%)1274 (28.2)936 (25.3)216 (42.6)*,**122 (38.2)*,**<0.001
 Prior MI, n (%)247 (5.5)139 (3.8)88 (17.4)*,**20 (6.3)*<0.001
 Prior PCI, n (%)1015 (22.4)731 (19.8)194 (38.3)*,**90 (28.2)*<0.001
 Prior CABG, n (%)194 (4.3)108 (2.9)67 (13.2)*,**19 (6.0)*<0.001
 Peripheral artery disease, n (%)467 (10.3)337 (9.1)84 (16.6)*,**46 (14.4)*<0.001
 COPD, n (%)447 (9.9)338 (9.1)66 (13.0)*43 (13.5)*0.002
 Prior stroke or TIA, n (%)517 (11.4)411 (11.1)70 (13.8)36 (11.3)0.203
Medication
 ACE inhibitor or ARB, n (%)2311 (51.1)1883 (51.0)257 (50.7)171 (53.6)0.649
 Beta blocker, n (%)1499 (33.1)1120 (30.3)257 (50.7)*,**122 (38.2)*<0.001
Blood test
 BNP, pg/mL270.9 [119.1, 579.8]254.4 [111.8, 551.6]505.4 [245.2, 955.5]*,**211.6 [97.7, 354.9]*<0.001
 eGFR, mL/min/1.73 m250.0 [38.0, 62.3]51.0 [39.0, 63.7]43.0 [32.0, 55.0]*,**48.0 [37.0, 59.9]*<0.001
 Hemoglobin, g/dL11.4 [10.2, 12.5]11.3 [10.2, 12.4]11.3 [10.2, 12.7]11.5 [10.6, 12.8]*,**<0.001
Electrical rhythm
 Atrial fibrillation, n (%)955 (21.1)643 (17.4)175 (34.5)*,**137 (42.9)*,**<0.001
 Right bundle branch block, n (%)752 (16.7)629 (17.1)86 (17.0)37 (11.6)*0.044
 Left bundle branch block, n (%)332 (7.4)216 (5.9)94 (18.6)*,**22 (6.9)<0.001
Echocardiographic data
 LVDs, mm28.5 [25.0, 34.0]28.0 [24.5, 32.0]40.0 [35.0, 45.0]*,**26.0 [23.0, 29.5]*,**<0.001
 LVDd, mm44.0 [40.0, 48.1]43.6 [40.0, 47.6]51.0 [46.0, 56.0]*,**40.0 [36.1, 44.0]*,**<0.001
 LVEF, %61.0 [49.0, 67.0]62.4 [54.0, 68.0]39.0 [32.0, 45.0]*,**64.0 [59.0, 68.0]*,**<0.001
 IVSd, mm11.9 [10.2, 13.0]12.0 [10.6, 13.0]10.9 [9.8, 12.0]*,**11.0 [10.0, 12.9]*,**<0.001
 PWd, mm11.0 [10.0, 12.3]11.0 [10.0, 12.8]10.0 [9.0, 12.0]*,**11.0 [9.5, 12.0]*,**<0.001
 LVM index, g/m2125.6 [104.3, 150.4]126.1 [105.5, 149.9]137.7 [114.5, 162.7]*,**99.1 [83.0, 120.9]*,**<0.001
 RWT0.53 [0.45, 0.62]0.53 [0.46, 0.62]0.42 [0.36, 0.49]*,**0.55 [0.47, 0.66]*,*<0.001
 SVi, mL/m244.5 [34.5, 54.0]47.1 [38.5, 55.9]34.6 [27.5, 43.6]*,**29.7 [25.5, 32.7]*,**<0.001
 LAD, mm42.0 [37.3, 46.4]41.9 [37.1, 46.0]44.0 [38.6, 48.6]*,**42.0 [36.0, 48.0]<0.001
 AV peak velocity, m/s4.6 [4.2, 5.2]4.8 [4.4, 5.3]3.6 [3.2, 3.9]*,**3.6 [3.3, 4.0]*,**<0.001
 Indexed AVA, cm2/m20.40 [0.33, 0.50]0.40 [0.32, 0.50]0.47 [0.40, 0.54]*,**0.42 [0.37, 0.50]*,**<0.001
 AV mean PG, mmHg50.2 [42.0, 63.2]54.3 [46.0, 66.7]29.2 [23.0, 34.1]*,**29.2 [22.7, 34.0]*,**<0.001
 AR ≥ moderate, n (%)491 (10.9)396 (10.7)69 (13.6)26 (8.2)0.039
 MR ≥ moderate, n (%)564 (12.5)407 (11.0)120 (23.7)*,**37 (11.6)<0.001
 sPAP, mmHg30.6 [25.0, 38.0]30.4 [25.2, 38.0]31.2 [24.0, 40.0]30.0 [24.8, 38.6]0.41
 OverallHG-AScLFLG-ASpLFLG-ASOverall
Number45233697507319P-value
Age, years85 [81, 88]85 [81, 88]84 [80, 87]*,**85 [82, 88]<0.001
Male, n (%)1431 (31.6)1065 (28.8)255 (50.3)*,**111 (34.8)*<0.001
Body mass index, kg/m222.0 [19.6, 24.5]22.1 [19.6, 24.5]21.2 [19.1, 24.1]*,**22.7 [20.0, 25.0]<0.001
Body surface area, m21.40 [1.30, 1.56]1.40 [1.30, 1.55]1.47 [1.30, 1.60]*1.46 [1.32, 1.58]*<0.001
NYHA functional Class III or IV, n (%)1962 (43.4)1516 (41.0)299 (59.0)*,**147 (46.1)<0.001
Clinical Frail Scale4 [3, 5]4 [3, 4]4 [3, 5]*,**4 [3, 4]<0.001
STS mortality score, %6.2 [4.2, 9.1]6.0 [4.2, 8.8]7.9 [5.0, 12.5]*,**6.3 [4.2, 9.4]<0.001
Past medical history
 Hypertension, n (%)3778 (83.5)3085 (83.4)426 (84.0)267 (83.7)0.944
 Dyslipidemia, n (%)2497 (55.2)2032 (55.0)297 (58.6)168 (52.7)0.196
 Diabetes mellitus, n (%)1274 (28.2)936 (25.3)216 (42.6)*,**122 (38.2)*,**<0.001
 Prior MI, n (%)247 (5.5)139 (3.8)88 (17.4)*,**20 (6.3)*<0.001
 Prior PCI, n (%)1015 (22.4)731 (19.8)194 (38.3)*,**90 (28.2)*<0.001
 Prior CABG, n (%)194 (4.3)108 (2.9)67 (13.2)*,**19 (6.0)*<0.001
 Peripheral artery disease, n (%)467 (10.3)337 (9.1)84 (16.6)*,**46 (14.4)*<0.001
 COPD, n (%)447 (9.9)338 (9.1)66 (13.0)*43 (13.5)*0.002
 Prior stroke or TIA, n (%)517 (11.4)411 (11.1)70 (13.8)36 (11.3)0.203
Medication
 ACE inhibitor or ARB, n (%)2311 (51.1)1883 (51.0)257 (50.7)171 (53.6)0.649
 Beta blocker, n (%)1499 (33.1)1120 (30.3)257 (50.7)*,**122 (38.2)*<0.001
Blood test
 BNP, pg/mL270.9 [119.1, 579.8]254.4 [111.8, 551.6]505.4 [245.2, 955.5]*,**211.6 [97.7, 354.9]*<0.001
 eGFR, mL/min/1.73 m250.0 [38.0, 62.3]51.0 [39.0, 63.7]43.0 [32.0, 55.0]*,**48.0 [37.0, 59.9]*<0.001
 Hemoglobin, g/dL11.4 [10.2, 12.5]11.3 [10.2, 12.4]11.3 [10.2, 12.7]11.5 [10.6, 12.8]*,**<0.001
Electrical rhythm
 Atrial fibrillation, n (%)955 (21.1)643 (17.4)175 (34.5)*,**137 (42.9)*,**<0.001
 Right bundle branch block, n (%)752 (16.7)629 (17.1)86 (17.0)37 (11.6)*0.044
 Left bundle branch block, n (%)332 (7.4)216 (5.9)94 (18.6)*,**22 (6.9)<0.001
Echocardiographic data
 LVDs, mm28.5 [25.0, 34.0]28.0 [24.5, 32.0]40.0 [35.0, 45.0]*,**26.0 [23.0, 29.5]*,**<0.001
 LVDd, mm44.0 [40.0, 48.1]43.6 [40.0, 47.6]51.0 [46.0, 56.0]*,**40.0 [36.1, 44.0]*,**<0.001
 LVEF, %61.0 [49.0, 67.0]62.4 [54.0, 68.0]39.0 [32.0, 45.0]*,**64.0 [59.0, 68.0]*,**<0.001
 IVSd, mm11.9 [10.2, 13.0]12.0 [10.6, 13.0]10.9 [9.8, 12.0]*,**11.0 [10.0, 12.9]*,**<0.001
 PWd, mm11.0 [10.0, 12.3]11.0 [10.0, 12.8]10.0 [9.0, 12.0]*,**11.0 [9.5, 12.0]*,**<0.001
 LVM index, g/m2125.6 [104.3, 150.4]126.1 [105.5, 149.9]137.7 [114.5, 162.7]*,**99.1 [83.0, 120.9]*,**<0.001
 RWT0.53 [0.45, 0.62]0.53 [0.46, 0.62]0.42 [0.36, 0.49]*,**0.55 [0.47, 0.66]*,*<0.001
 SVi, mL/m244.5 [34.5, 54.0]47.1 [38.5, 55.9]34.6 [27.5, 43.6]*,**29.7 [25.5, 32.7]*,**<0.001
 LAD, mm42.0 [37.3, 46.4]41.9 [37.1, 46.0]44.0 [38.6, 48.6]*,**42.0 [36.0, 48.0]<0.001
 AV peak velocity, m/s4.6 [4.2, 5.2]4.8 [4.4, 5.3]3.6 [3.2, 3.9]*,**3.6 [3.3, 4.0]*,**<0.001
 Indexed AVA, cm2/m20.40 [0.33, 0.50]0.40 [0.32, 0.50]0.47 [0.40, 0.54]*,**0.42 [0.37, 0.50]*,**<0.001
 AV mean PG, mmHg50.2 [42.0, 63.2]54.3 [46.0, 66.7]29.2 [23.0, 34.1]*,**29.2 [22.7, 34.0]*,**<0.001
 AR ≥ moderate, n (%)491 (10.9)396 (10.7)69 (13.6)26 (8.2)0.039
 MR ≥ moderate, n (%)564 (12.5)407 (11.0)120 (23.7)*,**37 (11.6)<0.001
 sPAP, mmHg30.6 [25.0, 38.0]30.4 [25.2, 38.0]31.2 [24.0, 40.0]30.0 [24.8, 38.6]0.41

Values are median [interquartile range; Q1, Q3] or number (%).

*P < 0.05 and **P < 0.001 compared to HG-AS.

ACE, angiotensin converting enzyme; AR, aortic valve regurgitation; ARB, angiotensin II receptor blocker; AV, aortic valve; AVA, aortic valve area; BNP, brain natriuretic peptide; CABG, coronary artery bypass graft; cLFLG, classical low-flow low-gradient; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; IVSd, interventricular septum diameter; HG, high gradient; LAD, left atrial diameter; LV, left ventricular; LVEF, LV ejection fraction; LVDd, diastolic left ventricular diameter; LVDs, systolic left ventricular diameter; LVM, LV mass; MI, myocardial infarction; MR, mitral regurgitation; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PG, pressure gradient; PWD, posterior wall diameter; RWT, relative wall thickness; sPAP, systolic pulmonary artery pressure; pLFLG, paradoxical low-flow low-gradient; STS, Society of Thoracic Surgeons; SVi, stroke volume index; TIA, transient ischaemic attack.

Table 1
Open in new tab

Baseline characteristics and echocardiographic parameters

 OverallHG-AScLFLG-ASpLFLG-ASOverall
Number45233697507319P-value
Age, years85 [81, 88]85 [81, 88]84 [80, 87]*,**85 [82, 88]<0.001
Male, n (%)1431 (31.6)1065 (28.8)255 (50.3)*,**111 (34.8)*<0.001
Body mass index, kg/m222.0 [19.6, 24.5]22.1 [19.6, 24.5]21.2 [19.1, 24.1]*,**22.7 [20.0, 25.0]<0.001
Body surface area, m21.40 [1.30, 1.56]1.40 [1.30, 1.55]1.47 [1.30, 1.60]*1.46 [1.32, 1.58]*<0.001
NYHA functional Class III or IV, n (%)1962 (43.4)1516 (41.0)299 (59.0)*,**147 (46.1)<0.001
Clinical Frail Scale4 [3, 5]4 [3, 4]4 [3, 5]*,**4 [3, 4]<0.001
STS mortality score, %6.2 [4.2, 9.1]6.0 [4.2, 8.8]7.9 [5.0, 12.5]*,**6.3 [4.2, 9.4]<0.001
Past medical history
 Hypertension, n (%)3778 (83.5)3085 (83.4)426 (84.0)267 (83.7)0.944
 Dyslipidemia, n (%)2497 (55.2)2032 (55.0)297 (58.6)168 (52.7)0.196
 Diabetes mellitus, n (%)1274 (28.2)936 (25.3)216 (42.6)*,**122 (38.2)*,**<0.001
 Prior MI, n (%)247 (5.5)139 (3.8)88 (17.4)*,**20 (6.3)*<0.001
 Prior PCI, n (%)1015 (22.4)731 (19.8)194 (38.3)*,**90 (28.2)*<0.001
 Prior CABG, n (%)194 (4.3)108 (2.9)67 (13.2)*,**19 (6.0)*<0.001
 Peripheral artery disease, n (%)467 (10.3)337 (9.1)84 (16.6)*,**46 (14.4)*<0.001
 COPD, n (%)447 (9.9)338 (9.1)66 (13.0)*43 (13.5)*0.002
 Prior stroke or TIA, n (%)517 (11.4)411 (11.1)70 (13.8)36 (11.3)0.203
Medication
 ACE inhibitor or ARB, n (%)2311 (51.1)1883 (51.0)257 (50.7)171 (53.6)0.649
 Beta blocker, n (%)1499 (33.1)1120 (30.3)257 (50.7)*,**122 (38.2)*<0.001
Blood test
 BNP, pg/mL270.9 [119.1, 579.8]254.4 [111.8, 551.6]505.4 [245.2, 955.5]*,**211.6 [97.7, 354.9]*<0.001
 eGFR, mL/min/1.73 m250.0 [38.0, 62.3]51.0 [39.0, 63.7]43.0 [32.0, 55.0]*,**48.0 [37.0, 59.9]*<0.001
 Hemoglobin, g/dL11.4 [10.2, 12.5]11.3 [10.2, 12.4]11.3 [10.2, 12.7]11.5 [10.6, 12.8]*,**<0.001
Electrical rhythm
 Atrial fibrillation, n (%)955 (21.1)643 (17.4)175 (34.5)*,**137 (42.9)*,**<0.001
 Right bundle branch block, n (%)752 (16.7)629 (17.1)86 (17.0)37 (11.6)*0.044
 Left bundle branch block, n (%)332 (7.4)216 (5.9)94 (18.6)*,**22 (6.9)<0.001
Echocardiographic data
 LVDs, mm28.5 [25.0, 34.0]28.0 [24.5, 32.0]40.0 [35.0, 45.0]*,**26.0 [23.0, 29.5]*,**<0.001
 LVDd, mm44.0 [40.0, 48.1]43.6 [40.0, 47.6]51.0 [46.0, 56.0]*,**40.0 [36.1, 44.0]*,**<0.001
 LVEF, %61.0 [49.0, 67.0]62.4 [54.0, 68.0]39.0 [32.0, 45.0]*,**64.0 [59.0, 68.0]*,**<0.001
 IVSd, mm11.9 [10.2, 13.0]12.0 [10.6, 13.0]10.9 [9.8, 12.0]*,**11.0 [10.0, 12.9]*,**<0.001
 PWd, mm11.0 [10.0, 12.3]11.0 [10.0, 12.8]10.0 [9.0, 12.0]*,**11.0 [9.5, 12.0]*,**<0.001
 LVM index, g/m2125.6 [104.3, 150.4]126.1 [105.5, 149.9]137.7 [114.5, 162.7]*,**99.1 [83.0, 120.9]*,**<0.001
 RWT0.53 [0.45, 0.62]0.53 [0.46, 0.62]0.42 [0.36, 0.49]*,**0.55 [0.47, 0.66]*,*<0.001
 SVi, mL/m244.5 [34.5, 54.0]47.1 [38.5, 55.9]34.6 [27.5, 43.6]*,**29.7 [25.5, 32.7]*,**<0.001
 LAD, mm42.0 [37.3, 46.4]41.9 [37.1, 46.0]44.0 [38.6, 48.6]*,**42.0 [36.0, 48.0]<0.001
 AV peak velocity, m/s4.6 [4.2, 5.2]4.8 [4.4, 5.3]3.6 [3.2, 3.9]*,**3.6 [3.3, 4.0]*,**<0.001
 Indexed AVA, cm2/m20.40 [0.33, 0.50]0.40 [0.32, 0.50]0.47 [0.40, 0.54]*,**0.42 [0.37, 0.50]*,**<0.001
 AV mean PG, mmHg50.2 [42.0, 63.2]54.3 [46.0, 66.7]29.2 [23.0, 34.1]*,**29.2 [22.7, 34.0]*,**<0.001
 AR ≥ moderate, n (%)491 (10.9)396 (10.7)69 (13.6)26 (8.2)0.039
 MR ≥ moderate, n (%)564 (12.5)407 (11.0)120 (23.7)*,**37 (11.6)<0.001
 sPAP, mmHg30.6 [25.0, 38.0]30.4 [25.2, 38.0]31.2 [24.0, 40.0]30.0 [24.8, 38.6]0.41
 OverallHG-AScLFLG-ASpLFLG-ASOverall
Number45233697507319P-value
Age, years85 [81, 88]85 [81, 88]84 [80, 87]*,**85 [82, 88]<0.001
Male, n (%)1431 (31.6)1065 (28.8)255 (50.3)*,**111 (34.8)*<0.001
Body mass index, kg/m222.0 [19.6, 24.5]22.1 [19.6, 24.5]21.2 [19.1, 24.1]*,**22.7 [20.0, 25.0]<0.001
Body surface area, m21.40 [1.30, 1.56]1.40 [1.30, 1.55]1.47 [1.30, 1.60]*1.46 [1.32, 1.58]*<0.001
NYHA functional Class III or IV, n (%)1962 (43.4)1516 (41.0)299 (59.0)*,**147 (46.1)<0.001
Clinical Frail Scale4 [3, 5]4 [3, 4]4 [3, 5]*,**4 [3, 4]<0.001
STS mortality score, %6.2 [4.2, 9.1]6.0 [4.2, 8.8]7.9 [5.0, 12.5]*,**6.3 [4.2, 9.4]<0.001
Past medical history
 Hypertension, n (%)3778 (83.5)3085 (83.4)426 (84.0)267 (83.7)0.944
 Dyslipidemia, n (%)2497 (55.2)2032 (55.0)297 (58.6)168 (52.7)0.196
 Diabetes mellitus, n (%)1274 (28.2)936 (25.3)216 (42.6)*,**122 (38.2)*,**<0.001
 Prior MI, n (%)247 (5.5)139 (3.8)88 (17.4)*,**20 (6.3)*<0.001
 Prior PCI, n (%)1015 (22.4)731 (19.8)194 (38.3)*,**90 (28.2)*<0.001
 Prior CABG, n (%)194 (4.3)108 (2.9)67 (13.2)*,**19 (6.0)*<0.001
 Peripheral artery disease, n (%)467 (10.3)337 (9.1)84 (16.6)*,**46 (14.4)*<0.001
 COPD, n (%)447 (9.9)338 (9.1)66 (13.0)*43 (13.5)*0.002
 Prior stroke or TIA, n (%)517 (11.4)411 (11.1)70 (13.8)36 (11.3)0.203
Medication
 ACE inhibitor or ARB, n (%)2311 (51.1)1883 (51.0)257 (50.7)171 (53.6)0.649
 Beta blocker, n (%)1499 (33.1)1120 (30.3)257 (50.7)*,**122 (38.2)*<0.001
Blood test
 BNP, pg/mL270.9 [119.1, 579.8]254.4 [111.8, 551.6]505.4 [245.2, 955.5]*,**211.6 [97.7, 354.9]*<0.001
 eGFR, mL/min/1.73 m250.0 [38.0, 62.3]51.0 [39.0, 63.7]43.0 [32.0, 55.0]*,**48.0 [37.0, 59.9]*<0.001
 Hemoglobin, g/dL11.4 [10.2, 12.5]11.3 [10.2, 12.4]11.3 [10.2, 12.7]11.5 [10.6, 12.8]*,**<0.001
Electrical rhythm
 Atrial fibrillation, n (%)955 (21.1)643 (17.4)175 (34.5)*,**137 (42.9)*,**<0.001
 Right bundle branch block, n (%)752 (16.7)629 (17.1)86 (17.0)37 (11.6)*0.044
 Left bundle branch block, n (%)332 (7.4)216 (5.9)94 (18.6)*,**22 (6.9)<0.001
Echocardiographic data
 LVDs, mm28.5 [25.0, 34.0]28.0 [24.5, 32.0]40.0 [35.0, 45.0]*,**26.0 [23.0, 29.5]*,**<0.001
 LVDd, mm44.0 [40.0, 48.1]43.6 [40.0, 47.6]51.0 [46.0, 56.0]*,**40.0 [36.1, 44.0]*,**<0.001
 LVEF, %61.0 [49.0, 67.0]62.4 [54.0, 68.0]39.0 [32.0, 45.0]*,**64.0 [59.0, 68.0]*,**<0.001
 IVSd, mm11.9 [10.2, 13.0]12.0 [10.6, 13.0]10.9 [9.8, 12.0]*,**11.0 [10.0, 12.9]*,**<0.001
 PWd, mm11.0 [10.0, 12.3]11.0 [10.0, 12.8]10.0 [9.0, 12.0]*,**11.0 [9.5, 12.0]*,**<0.001
 LVM index, g/m2125.6 [104.3, 150.4]126.1 [105.5, 149.9]137.7 [114.5, 162.7]*,**99.1 [83.0, 120.9]*,**<0.001
 RWT0.53 [0.45, 0.62]0.53 [0.46, 0.62]0.42 [0.36, 0.49]*,**0.55 [0.47, 0.66]*,*<0.001
 SVi, mL/m244.5 [34.5, 54.0]47.1 [38.5, 55.9]34.6 [27.5, 43.6]*,**29.7 [25.5, 32.7]*,**<0.001
 LAD, mm42.0 [37.3, 46.4]41.9 [37.1, 46.0]44.0 [38.6, 48.6]*,**42.0 [36.0, 48.0]<0.001
 AV peak velocity, m/s4.6 [4.2, 5.2]4.8 [4.4, 5.3]3.6 [3.2, 3.9]*,**3.6 [3.3, 4.0]*,**<0.001
 Indexed AVA, cm2/m20.40 [0.33, 0.50]0.40 [0.32, 0.50]0.47 [0.40, 0.54]*,**0.42 [0.37, 0.50]*,**<0.001
 AV mean PG, mmHg50.2 [42.0, 63.2]54.3 [46.0, 66.7]29.2 [23.0, 34.1]*,**29.2 [22.7, 34.0]*,**<0.001
 AR ≥ moderate, n (%)491 (10.9)396 (10.7)69 (13.6)26 (8.2)0.039
 MR ≥ moderate, n (%)564 (12.5)407 (11.0)120 (23.7)*,**37 (11.6)<0.001
 sPAP, mmHg30.6 [25.0, 38.0]30.4 [25.2, 38.0]31.2 [24.0, 40.0]30.0 [24.8, 38.6]0.41

Values are median [interquartile range; Q1, Q3] or number (%).

*P < 0.05 and **P < 0.001 compared to HG-AS.

ACE, angiotensin converting enzyme; AR, aortic valve regurgitation; ARB, angiotensin II receptor blocker; AV, aortic valve; AVA, aortic valve area; BNP, brain natriuretic peptide; CABG, coronary artery bypass graft; cLFLG, classical low-flow low-gradient; COPD, chronic obstructive pulmonary disease; eGFR, estimated glomerular filtration rate; IVSd, interventricular septum diameter; HG, high gradient; LAD, left atrial diameter; LV, left ventricular; LVEF, LV ejection fraction; LVDd, diastolic left ventricular diameter; LVDs, systolic left ventricular diameter; LVM, LV mass; MI, myocardial infarction; MR, mitral regurgitation; NYHA, New York Heart Association; PCI, percutaneous coronary intervention; PG, pressure gradient; PWD, posterior wall diameter; RWT, relative wall thickness; sPAP, systolic pulmonary artery pressure; pLFLG, paradoxical low-flow low-gradient; STS, Society of Thoracic Surgeons; SVi, stroke volume index; TIA, transient ischaemic attack.

Clinical outcomes

The median follow-up durations were 715 (377–748), 496 (363–737), and 715 (371–750) days for HG-AS, cLFLG-AS, and pLFLG-AS, respectively. The fraction of NYHA III or IV in cLFLG-AS and pLFLG-AS was significantly higher than that in HG-AS at the 1- and 2-year follow-up periods (1 year: cLFLG-AS vs. HG-AS, P = 0.001; pLFLG-AS vs. HG-AS, P = 0.019 and 2 years: cLFLG-AS vs. HG-AS, P = 0.003; pLFLG-AS vs. HG-AS, P = 0.039; see Supplementary data online, Figure S2). Kaplan–Meier curves for all-cause death, CV death, HHF, and composite events demonstrated significant differences, with a similar trend among the three groups, indicating that cLFLG-AS, pLFLG-AS, and HG-AS were sequentially from worst to best (log-rank P < 0.001 for all; see Supplementary data online, Figure S3). After multivariate adjustment, cLFLG-AS and pLFLG-AS conferred a significantly higher risk of 2-year adverse events compared with HG-AS [all-cause death: cLFLG-AS (HR 1.53; 95% CI 1.27–1.85), pLFLG-AS (HR 1.55; 95% CI 1.22–1.97), CV death: cLFLG-AS (HR 1.98; 95% CI 1.47–2.66), pLFLG-AS (HR 1.97; 95% CI 1.36–2.88), HHF: cLFLG-AS (HR 2.17; 95% CI 1.64–2.88), pLFLG-AS (HR 1.95; 95% CI 1.38–2.77), composite events: cLFLG-AS (HR 2.05; 95% CI 1.65–2.54), pLFLG-AS (HR 1.90; 95% CI 1.44–2.94)] (Figure 1). Regarding the impact of LV geometry at baseline, after multivariate adjustment, compared with normal geometry as reference, there were no significant differences in 2-year composite events in other three kinds of LV geometry in overall, HG-AS and cLFLG-AS (see Supplementary data online, Figure S4A–C). In pLFLG-AS, a significant difference was observed in eccentric hypertrophy vs. normal, however, very few patients had eccentric hypertrophy at baseline (see Supplementary data online, Figure S4D).

Kaplan–Meier curves of clinical outcomes in LFLG-AS compared to HG-AS after adjustment with clinical factors. A) All-cause death, B) CV death, C) heart failure hospitalization, and D) composite events of CV death and heart failure hospitalization. Adjustment was performed with age, sex, body mass index, STS score, and New York Heart Association III or IV. cLFLG-AS, classical low-flow low-gradient aortic stenosis; CV, cardiovascular; HG-AS, high gradient aortic stenosis; pLFLG-AS, paradoxical low-flow low-gradient aortic stenosis.
Figure 1

Kaplan–Meier curves of clinical outcomes in LFLG-AS compared to HG-AS after adjustment with clinical factors. A) All-cause death, B) CV death, C) heart failure hospitalization, and D) composite events of CV death and heart failure hospitalization. Adjustment was performed with age, sex, body mass index, STS score, and New York Heart Association III or IV. cLFLG-AS, classical low-flow low-gradient aortic stenosis; CV, cardiovascular; HG-AS, high gradient aortic stenosis; pLFLG-AS, paradoxical low-flow low-gradient aortic stenosis.

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Echocardiographic outcomes

Serial changes of echocardiographic parameters in each group

Figure 2 and Table 2 show the serial changes in the echocardiographic parameters until 1 year after TAVI. In the HG-AS group, the improvement in iAVA, MPG, LVEF, and SVi and the reverse remodelling of the left chambers were significantly maintained for 1 year after discharge (iAVA, MPG, SVi, LVDs, LVDd, LAD, LVMi, and RWT P < 0.001 for all, LVEF P = 0.001). In contrast, the cLFLG-AS group had no significant improvement of iAVA, MPG, LVEF, and RWT (P = 0.412, P = 0.226, P = 0.391, and P = 0.061, respectively), whereas the pLFLG-AS group showed no significant differences in iAVA, MPG, SVi, and LAD (P = 0.079, P = 0.656, P = 0.158, and P = 0.622, respectively).

Serial echocardiographic parameters during 1 year in three groups. A) Indexed AVA, B) mean AV-PG, C) SV index, D) LVEF, E) LV mass index, and F) LA diameter. AV, aortic valve; AVA, aortic valve area; cLFLG-AS, classical low-flow low-gradient aortic stenosis; HG-AS, high gradient aortic stenosis; LA, left atrial; LV, left ventricular; LVEF, left ventricular ejection fraction; PG, pressure gradient; pLFLG-AS, paradoxical low-flow low-gradient aortic stenosis; SV, stroke volume.
Figure 2

Serial echocardiographic parameters during 1 year in three groups. A) Indexed AVA, B) mean AV-PG, C) SV index, D) LVEF, E) LV mass index, and F) LA diameter. AV, aortic valve; AVA, aortic valve area; cLFLG-AS, classical low-flow low-gradient aortic stenosis; HG-AS, high gradient aortic stenosis; LA, left atrial; LV, left ventricular; LVEF, left ventricular ejection fraction; PG, pressure gradient; pLFLG-AS, paradoxical low-flow low-gradient aortic stenosis; SV, stroke volume.

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Table 2
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Serial echocardiographic parameters

 HG-AScLFLG-ASpLFLG-AS
Post1 yearP-value
pre vs. post		P-value
post vs. 1 year		post1 yearP-value
pre vs. post		P-value
post vs. 1 year		post1 yearP-value
pre vs. post		P-value
post vs. 1 year
iAVA, cm2/m21.13
[0.97, 1.34]		1.10
[0.93, 1.32]		<0.001<0.0011.16
[0.96, 1.36]		1.10
[0.93, 1.31]		<0.0010.4121.10
[0.93, 1.29]		1.03
[0.89, 1.23]		<0.0010.079
MPG, mmHg11.0
[8.0, 14.0]		10.5
[8.0, 14.0]		<0.001<0.0018.0
[6.0, 10.3]		8.0
[6.0, 10.1]		<0.0010.2268.0
[6.0, 11.3]		9.0
[6.4, 11.8]		<0.0010.656
LVDs, mm27.5
[24.8, 31.0]		26.1
[23.1, 29.4]		<0.001<0.00137.8
[32.1, 43.5]		33.0
[28.0, 39.0]		<0.001<0.00127.0
[23.0, 29.7]		26.0
[23.0, 29.0]		0.0010.004
LVDd, mm43.2
[40.0, 47.0]		42.0
[39.0, 46.0]		<0.001<0.00150.0
[45.6, 55.5]		46.3
[42.0, 51.7]		0.94<0.00141.0
[37.7, 44.8]		41.5
[38.0, 45.0]		0.673<0.001
LVEF, %63.0
[56.0, 67.5]		64.6
[60.0, 68.2]		<0.0010.00143.0
[35.9, 49.5]		49.6
[42.8, 57.0]		<0.0010.39163.5
[59.1, 67.8]		64.0
[59.1, 67.4]		0.0080.023
SVi, mL/m249.3
[40.2, 57.9]		50.0
[40.9, 60.0]		<0.001<0.00143.3
[34.2, 52.5]		43.7
[36.1, 52.1]		<0.0010.0436.7
[29.1, 44.8]		39.8
[33.5, 51.5]		<0.0010.158
LVMi, g/m2123.8
[104.3, 146.7]		103.5
[87.2, 123.0]		<0.001<0.001139.5
[119.4, 164.5]		120.1
[98.3, 145.2]		0.11<0.001102.9
[86.5, 123.4]		95.1
[78.4, 115.1]		0.070<0.001
RWT0.51
[0.44, 0.59]		0.48
[0.42, 0.55]		<0.001<0.0010.42
[0.36, 0.50]		0.43
[0.36, 0.50]		0.0050.0610.52
[0.46, 0.59]		0.48
[0.42, 0.53]		<0.0010.031
LAD, mm42.0
[37.7, 46.0]		41.0
[36.7, 45.1]		0.121<0.00144.0
[39.9, 48.0]		42.0
[37.0, 48.0]		0.4560.00742.0
[38.0, 47.4]		43.0
[38.1, 47.8]		0.5370.622
 HG-AScLFLG-ASpLFLG-AS
Post1 yearP-value
pre vs. post		P-value
post vs. 1 year		post1 yearP-value
pre vs. post		P-value
post vs. 1 year		post1 yearP-value
pre vs. post		P-value
post vs. 1 year
iAVA, cm2/m21.13
[0.97, 1.34]		1.10
[0.93, 1.32]		<0.001<0.0011.16
[0.96, 1.36]		1.10
[0.93, 1.31]		<0.0010.4121.10
[0.93, 1.29]		1.03
[0.89, 1.23]		<0.0010.079
MPG, mmHg11.0
[8.0, 14.0]		10.5
[8.0, 14.0]		<0.001<0.0018.0
[6.0, 10.3]		8.0
[6.0, 10.1]		<0.0010.2268.0
[6.0, 11.3]		9.0
[6.4, 11.8]		<0.0010.656
LVDs, mm27.5
[24.8, 31.0]		26.1
[23.1, 29.4]		<0.001<0.00137.8
[32.1, 43.5]		33.0
[28.0, 39.0]		<0.001<0.00127.0
[23.0, 29.7]		26.0
[23.0, 29.0]		0.0010.004
LVDd, mm43.2
[40.0, 47.0]		42.0
[39.0, 46.0]		<0.001<0.00150.0
[45.6, 55.5]		46.3
[42.0, 51.7]		0.94<0.00141.0
[37.7, 44.8]		41.5
[38.0, 45.0]		0.673<0.001
LVEF, %63.0
[56.0, 67.5]		64.6
[60.0, 68.2]		<0.0010.00143.0
[35.9, 49.5]		49.6
[42.8, 57.0]		<0.0010.39163.5
[59.1, 67.8]		64.0
[59.1, 67.4]		0.0080.023
SVi, mL/m249.3
[40.2, 57.9]		50.0
[40.9, 60.0]		<0.001<0.00143.3
[34.2, 52.5]		43.7
[36.1, 52.1]		<0.0010.0436.7
[29.1, 44.8]		39.8
[33.5, 51.5]		<0.0010.158
LVMi, g/m2123.8
[104.3, 146.7]		103.5
[87.2, 123.0]		<0.001<0.001139.5
[119.4, 164.5]		120.1
[98.3, 145.2]		0.11<0.001102.9
[86.5, 123.4]		95.1
[78.4, 115.1]		0.070<0.001
RWT0.51
[0.44, 0.59]		0.48
[0.42, 0.55]		<0.001<0.0010.42
[0.36, 0.50]		0.43
[0.36, 0.50]		0.0050.0610.52
[0.46, 0.59]		0.48
[0.42, 0.53]		<0.0010.031
LAD, mm42.0
[37.7, 46.0]		41.0
[36.7, 45.1]		0.121<0.00144.0
[39.9, 48.0]		42.0
[37.0, 48.0]		0.4560.00742.0
[38.0, 47.4]		43.0
[38.1, 47.8]		0.5370.622

Values are median [interquartile range; Q1, Q3]. Abbreviations are shown in Table 1.

Table 2
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Serial echocardiographic parameters

 HG-AScLFLG-ASpLFLG-AS
Post1 yearP-value
pre vs. post		P-value
post vs. 1 year		post1 yearP-value
pre vs. post		P-value
post vs. 1 year		post1 yearP-value
pre vs. post		P-value
post vs. 1 year
iAVA, cm2/m21.13
[0.97, 1.34]		1.10
[0.93, 1.32]		<0.001<0.0011.16
[0.96, 1.36]		1.10
[0.93, 1.31]		<0.0010.4121.10
[0.93, 1.29]		1.03
[0.89, 1.23]		<0.0010.079
MPG, mmHg11.0
[8.0, 14.0]		10.5
[8.0, 14.0]		<0.001<0.0018.0
[6.0, 10.3]		8.0
[6.0, 10.1]		<0.0010.2268.0
[6.0, 11.3]		9.0
[6.4, 11.8]		<0.0010.656
LVDs, mm27.5
[24.8, 31.0]		26.1
[23.1, 29.4]		<0.001<0.00137.8
[32.1, 43.5]		33.0
[28.0, 39.0]		<0.001<0.00127.0
[23.0, 29.7]		26.0
[23.0, 29.0]		0.0010.004
LVDd, mm43.2
[40.0, 47.0]		42.0
[39.0, 46.0]		<0.001<0.00150.0
[45.6, 55.5]		46.3
[42.0, 51.7]		0.94<0.00141.0
[37.7, 44.8]		41.5
[38.0, 45.0]		0.673<0.001
LVEF, %63.0
[56.0, 67.5]		64.6
[60.0, 68.2]		<0.0010.00143.0
[35.9, 49.5]		49.6
[42.8, 57.0]		<0.0010.39163.5
[59.1, 67.8]		64.0
[59.1, 67.4]		0.0080.023
SVi, mL/m249.3
[40.2, 57.9]		50.0
[40.9, 60.0]		<0.001<0.00143.3
[34.2, 52.5]		43.7
[36.1, 52.1]		<0.0010.0436.7
[29.1, 44.8]		39.8
[33.5, 51.5]		<0.0010.158
LVMi, g/m2123.8
[104.3, 146.7]		103.5
[87.2, 123.0]		<0.001<0.001139.5
[119.4, 164.5]		120.1
[98.3, 145.2]		0.11<0.001102.9
[86.5, 123.4]		95.1
[78.4, 115.1]		0.070<0.001
RWT0.51
[0.44, 0.59]		0.48
[0.42, 0.55]		<0.001<0.0010.42
[0.36, 0.50]		0.43
[0.36, 0.50]		0.0050.0610.52
[0.46, 0.59]		0.48
[0.42, 0.53]		<0.0010.031
LAD, mm42.0
[37.7, 46.0]		41.0
[36.7, 45.1]		0.121<0.00144.0
[39.9, 48.0]		42.0
[37.0, 48.0]		0.4560.00742.0
[38.0, 47.4]		43.0
[38.1, 47.8]		0.5370.622
 HG-AScLFLG-ASpLFLG-AS
Post1 yearP-value
pre vs. post		P-value
post vs. 1 year		post1 yearP-value
pre vs. post		P-value
post vs. 1 year		post1 yearP-value
pre vs. post		P-value
post vs. 1 year
iAVA, cm2/m21.13
[0.97, 1.34]		1.10
[0.93, 1.32]		<0.001<0.0011.16
[0.96, 1.36]		1.10
[0.93, 1.31]		<0.0010.4121.10
[0.93, 1.29]		1.03
[0.89, 1.23]		<0.0010.079
MPG, mmHg11.0
[8.0, 14.0]		10.5
[8.0, 14.0]		<0.001<0.0018.0
[6.0, 10.3]		8.0
[6.0, 10.1]		<0.0010.2268.0
[6.0, 11.3]		9.0
[6.4, 11.8]		<0.0010.656
LVDs, mm27.5
[24.8, 31.0]		26.1
[23.1, 29.4]		<0.001<0.00137.8
[32.1, 43.5]		33.0
[28.0, 39.0]		<0.001<0.00127.0
[23.0, 29.7]		26.0
[23.0, 29.0]		0.0010.004
LVDd, mm43.2
[40.0, 47.0]		42.0
[39.0, 46.0]		<0.001<0.00150.0
[45.6, 55.5]		46.3
[42.0, 51.7]		0.94<0.00141.0
[37.7, 44.8]		41.5
[38.0, 45.0]		0.673<0.001
LVEF, %63.0
[56.0, 67.5]		64.6
[60.0, 68.2]		<0.0010.00143.0
[35.9, 49.5]		49.6
[42.8, 57.0]		<0.0010.39163.5
[59.1, 67.8]		64.0
[59.1, 67.4]		0.0080.023
SVi, mL/m249.3
[40.2, 57.9]		50.0
[40.9, 60.0]		<0.001<0.00143.3
[34.2, 52.5]		43.7
[36.1, 52.1]		<0.0010.0436.7
[29.1, 44.8]		39.8
[33.5, 51.5]		<0.0010.158
LVMi, g/m2123.8
[104.3, 146.7]		103.5
[87.2, 123.0]		<0.001<0.001139.5
[119.4, 164.5]		120.1
[98.3, 145.2]		0.11<0.001102.9
[86.5, 123.4]		95.1
[78.4, 115.1]		0.070<0.001
RWT0.51
[0.44, 0.59]		0.48
[0.42, 0.55]		<0.001<0.0010.42
[0.36, 0.50]		0.43
[0.36, 0.50]		0.0050.0610.52
[0.46, 0.59]		0.48
[0.42, 0.53]		<0.0010.031
LAD, mm42.0
[37.7, 46.0]		41.0
[36.7, 45.1]		0.121<0.00144.0
[39.9, 48.0]		42.0
[37.0, 48.0]		0.4560.00742.0
[38.0, 47.4]		43.0
[38.1, 47.8]		0.5370.622

Values are median [interquartile range; Q1, Q3]. Abbreviations are shown in Table 1.

Cardiac reversibility in both types of LFLG-AS compared with HG-AS

Table 3 shows the interval difference in echocardiographic parameters between baseline and post-procedure and between post-procedure and 1 year post-TAVI in both types of LFLG-AS compared with HG-AS. After discharge, the cLFLG-AS group showed a greater reduction in LVDs and LVDd (P < 0.001 for both) and increased LVEF (P < 0.001); however, no significant difference was observed in LAD, SVi, and LVMi (P = 0.705, P = 0.821, and P = 0.915, respectively). In contrast, the pLFLG-AS group showed less reduction in LVDs, LVDd, and LAD (P = 0.039, P = 0.001, and P = 0.014, respectively), less improvement in LVEF and LVMi (P = 0.045 and P < 0.001, respectively), and no significant difference in SVi (P = 0.364).

Table 3
Open in new tab

Difference value in echocardiographic parameters according to flow and gradient pattern

 HG-AScLFLG-ASpLFLG-ASOverall
P-value
ΔiAVA, cm2/m2 [post-pre]0.72 [0.55, 0.92]0.69 [0.51, 0.92]0.65 [0.50, 0.84]*,**<0.001
ΔiAVA, cm2/m2 [1 year-post]−0.02 [−0.18, 0.14]−0.01 [−0.22, 0.14]−0.01 [−0.19, 0.13]0.774
ΔMPG, mmHg [post-pre]−43.70 [−55.00, −35.90]−20.90 [−25.63, −14.20]*,**−19.70 [−25.02, −13.90]*,**<0.001
ΔMPG, mmHg [1 year-post]−0.20 [−3.00, 2.00]0.00 [−2.00, 2.00]0.35 [−1.63, 2.90]*0.002
ΔLVDs, mm [post-pre]−0.60 [−3.00, 1.00]−1.05 [−4.00, 0.50]*,**0.00 [−2.00, 2.00]*,**<0.001
ΔLVDs, mm [1 year-post]−1.00 [−3.90, 1.30]−3.00 [−7.00, 0.55]*,**−0.40 [−2.00, 1.00]*<0.001
ΔLVDd, mm [post-pre]0.00 [−2.00, 2.00]−0.10 [−2.00, 2.00]1.00 [−1.00, 3.00]*,**<0.001
ΔLVDd, mm [1 year-post]−1.00 [−4.00, 1.35]−2.80 [−6.00, 0.40]*,**0.00 [−2.70, 2.00]*<0.001
ΔLVEF, % [post-pre]1.00 [−2.40, 5.16]3.30 [0.00, 9.10]*,**0.00 [−3.00, 3.00]*<0.001
ΔLVEF, % [1 year-post]0.30 [−3.80, 5.05]4.65 [−1.00, 10.43]*,**0.00 [−5.00, 2.55]*<0.001
ΔSVi, mL/m2 [post-pre]1.46 [−6.47, 9.81]6.26 [0.00, 13.82]*,**7.07 [1.05, 15.20]*,**<0.001
ΔSVi, mL/m2 [1 year-post]1.54 [−7.40, 11.57]2.14 [−6.28, 11.25]2.41 [−5.35, 11.02]0.654
ΔLVM index, g/m2 [post-pre]−2.34 [−14.93, 8.13]−0.43 [−14.32, 12.32]1.07 [−9.20, 13.93]*0.001
ΔLVM index, g/m2 [1 year-post]−15.45 [−32.60, −0.56]−14.52 [−37.48, 0.19]−4.70 [−15.78, 9.36]*,**<0.001
ΔRWT [post-pre]−0.02 [−0.08, 0.03]−0.01 [−0.07, 0.04]*−0.03 [−0.09, 0.02]0.008
ΔRWT [1 year-post]−0.02 [−0.08, 0.03]0.01 [−0.04, 0.06]*,**−0.02 [−0.06, 0.03]<0.001
ΔLAD, mm [post-pre]0.00 [−3.00, 3.00]0.60 [−2.40, 3.20]0.05 [−2.00, 3.92]0.053
ΔLAD, mm [1 year-post]−1.00 [−4.00, 2.77]−1.20 [−5.15, 3.12]0.00 [−3.00, 3.20]*0.045
 HG-AScLFLG-ASpLFLG-ASOverall
P-value
ΔiAVA, cm2/m2 [post-pre]0.72 [0.55, 0.92]0.69 [0.51, 0.92]0.65 [0.50, 0.84]*,**<0.001
ΔiAVA, cm2/m2 [1 year-post]−0.02 [−0.18, 0.14]−0.01 [−0.22, 0.14]−0.01 [−0.19, 0.13]0.774
ΔMPG, mmHg [post-pre]−43.70 [−55.00, −35.90]−20.90 [−25.63, −14.20]*,**−19.70 [−25.02, −13.90]*,**<0.001
ΔMPG, mmHg [1 year-post]−0.20 [−3.00, 2.00]0.00 [−2.00, 2.00]0.35 [−1.63, 2.90]*0.002
ΔLVDs, mm [post-pre]−0.60 [−3.00, 1.00]−1.05 [−4.00, 0.50]*,**0.00 [−2.00, 2.00]*,**<0.001
ΔLVDs, mm [1 year-post]−1.00 [−3.90, 1.30]−3.00 [−7.00, 0.55]*,**−0.40 [−2.00, 1.00]*<0.001
ΔLVDd, mm [post-pre]0.00 [−2.00, 2.00]−0.10 [−2.00, 2.00]1.00 [−1.00, 3.00]*,**<0.001
ΔLVDd, mm [1 year-post]−1.00 [−4.00, 1.35]−2.80 [−6.00, 0.40]*,**0.00 [−2.70, 2.00]*<0.001
ΔLVEF, % [post-pre]1.00 [−2.40, 5.16]3.30 [0.00, 9.10]*,**0.00 [−3.00, 3.00]*<0.001
ΔLVEF, % [1 year-post]0.30 [−3.80, 5.05]4.65 [−1.00, 10.43]*,**0.00 [−5.00, 2.55]*<0.001
ΔSVi, mL/m2 [post-pre]1.46 [−6.47, 9.81]6.26 [0.00, 13.82]*,**7.07 [1.05, 15.20]*,**<0.001
ΔSVi, mL/m2 [1 year-post]1.54 [−7.40, 11.57]2.14 [−6.28, 11.25]2.41 [−5.35, 11.02]0.654
ΔLVM index, g/m2 [post-pre]−2.34 [−14.93, 8.13]−0.43 [−14.32, 12.32]1.07 [−9.20, 13.93]*0.001
ΔLVM index, g/m2 [1 year-post]−15.45 [−32.60, −0.56]−14.52 [−37.48, 0.19]−4.70 [−15.78, 9.36]*,**<0.001
ΔRWT [post-pre]−0.02 [−0.08, 0.03]−0.01 [−0.07, 0.04]*−0.03 [−0.09, 0.02]0.008
ΔRWT [1 year-post]−0.02 [−0.08, 0.03]0.01 [−0.04, 0.06]*,**−0.02 [−0.06, 0.03]<0.001
ΔLAD, mm [post-pre]0.00 [−3.00, 3.00]0.60 [−2.40, 3.20]0.05 [−2.00, 3.92]0.053
ΔLAD, mm [1 year-post]−1.00 [−4.00, 2.77]−1.20 [−5.15, 3.12]0.00 [−3.00, 3.20]*0.045

Values are median [interquartile range; Q1, Q3].

*P < 0.05 and **P < 0.001 compared to HG-AS.

Abbreviations are shown in Table 1.

Table 3
Open in new tab

Difference value in echocardiographic parameters according to flow and gradient pattern

 HG-AScLFLG-ASpLFLG-ASOverall
P-value
ΔiAVA, cm2/m2 [post-pre]0.72 [0.55, 0.92]0.69 [0.51, 0.92]0.65 [0.50, 0.84]*,**<0.001
ΔiAVA, cm2/m2 [1 year-post]−0.02 [−0.18, 0.14]−0.01 [−0.22, 0.14]−0.01 [−0.19, 0.13]0.774
ΔMPG, mmHg [post-pre]−43.70 [−55.00, −35.90]−20.90 [−25.63, −14.20]*,**−19.70 [−25.02, −13.90]*,**<0.001
ΔMPG, mmHg [1 year-post]−0.20 [−3.00, 2.00]0.00 [−2.00, 2.00]0.35 [−1.63, 2.90]*0.002
ΔLVDs, mm [post-pre]−0.60 [−3.00, 1.00]−1.05 [−4.00, 0.50]*,**0.00 [−2.00, 2.00]*,**<0.001
ΔLVDs, mm [1 year-post]−1.00 [−3.90, 1.30]−3.00 [−7.00, 0.55]*,**−0.40 [−2.00, 1.00]*<0.001
ΔLVDd, mm [post-pre]0.00 [−2.00, 2.00]−0.10 [−2.00, 2.00]1.00 [−1.00, 3.00]*,**<0.001
ΔLVDd, mm [1 year-post]−1.00 [−4.00, 1.35]−2.80 [−6.00, 0.40]*,**0.00 [−2.70, 2.00]*<0.001
ΔLVEF, % [post-pre]1.00 [−2.40, 5.16]3.30 [0.00, 9.10]*,**0.00 [−3.00, 3.00]*<0.001
ΔLVEF, % [1 year-post]0.30 [−3.80, 5.05]4.65 [−1.00, 10.43]*,**0.00 [−5.00, 2.55]*<0.001
ΔSVi, mL/m2 [post-pre]1.46 [−6.47, 9.81]6.26 [0.00, 13.82]*,**7.07 [1.05, 15.20]*,**<0.001
ΔSVi, mL/m2 [1 year-post]1.54 [−7.40, 11.57]2.14 [−6.28, 11.25]2.41 [−5.35, 11.02]0.654
ΔLVM index, g/m2 [post-pre]−2.34 [−14.93, 8.13]−0.43 [−14.32, 12.32]1.07 [−9.20, 13.93]*0.001
ΔLVM index, g/m2 [1 year-post]−15.45 [−32.60, −0.56]−14.52 [−37.48, 0.19]−4.70 [−15.78, 9.36]*,**<0.001
ΔRWT [post-pre]−0.02 [−0.08, 0.03]−0.01 [−0.07, 0.04]*−0.03 [−0.09, 0.02]0.008
ΔRWT [1 year-post]−0.02 [−0.08, 0.03]0.01 [−0.04, 0.06]*,**−0.02 [−0.06, 0.03]<0.001
ΔLAD, mm [post-pre]0.00 [−3.00, 3.00]0.60 [−2.40, 3.20]0.05 [−2.00, 3.92]0.053
ΔLAD, mm [1 year-post]−1.00 [−4.00, 2.77]−1.20 [−5.15, 3.12]0.00 [−3.00, 3.20]*0.045
 HG-AScLFLG-ASpLFLG-ASOverall
P-value
ΔiAVA, cm2/m2 [post-pre]0.72 [0.55, 0.92]0.69 [0.51, 0.92]0.65 [0.50, 0.84]*,**<0.001
ΔiAVA, cm2/m2 [1 year-post]−0.02 [−0.18, 0.14]−0.01 [−0.22, 0.14]−0.01 [−0.19, 0.13]0.774
ΔMPG, mmHg [post-pre]−43.70 [−55.00, −35.90]−20.90 [−25.63, −14.20]*,**−19.70 [−25.02, −13.90]*,**<0.001
ΔMPG, mmHg [1 year-post]−0.20 [−3.00, 2.00]0.00 [−2.00, 2.00]0.35 [−1.63, 2.90]*0.002
ΔLVDs, mm [post-pre]−0.60 [−3.00, 1.00]−1.05 [−4.00, 0.50]*,**0.00 [−2.00, 2.00]*,**<0.001
ΔLVDs, mm [1 year-post]−1.00 [−3.90, 1.30]−3.00 [−7.00, 0.55]*,**−0.40 [−2.00, 1.00]*<0.001
ΔLVDd, mm [post-pre]0.00 [−2.00, 2.00]−0.10 [−2.00, 2.00]1.00 [−1.00, 3.00]*,**<0.001
ΔLVDd, mm [1 year-post]−1.00 [−4.00, 1.35]−2.80 [−6.00, 0.40]*,**0.00 [−2.70, 2.00]*<0.001
ΔLVEF, % [post-pre]1.00 [−2.40, 5.16]3.30 [0.00, 9.10]*,**0.00 [−3.00, 3.00]*<0.001
ΔLVEF, % [1 year-post]0.30 [−3.80, 5.05]4.65 [−1.00, 10.43]*,**0.00 [−5.00, 2.55]*<0.001
ΔSVi, mL/m2 [post-pre]1.46 [−6.47, 9.81]6.26 [0.00, 13.82]*,**7.07 [1.05, 15.20]*,**<0.001
ΔSVi, mL/m2 [1 year-post]1.54 [−7.40, 11.57]2.14 [−6.28, 11.25]2.41 [−5.35, 11.02]0.654
ΔLVM index, g/m2 [post-pre]−2.34 [−14.93, 8.13]−0.43 [−14.32, 12.32]1.07 [−9.20, 13.93]*0.001
ΔLVM index, g/m2 [1 year-post]−15.45 [−32.60, −0.56]−14.52 [−37.48, 0.19]−4.70 [−15.78, 9.36]*,**<0.001
ΔRWT [post-pre]−0.02 [−0.08, 0.03]−0.01 [−0.07, 0.04]*−0.03 [−0.09, 0.02]0.008
ΔRWT [1 year-post]−0.02 [−0.08, 0.03]0.01 [−0.04, 0.06]*,**−0.02 [−0.06, 0.03]<0.001
ΔLAD, mm [post-pre]0.00 [−3.00, 3.00]0.60 [−2.40, 3.20]0.05 [−2.00, 3.92]0.053
ΔLAD, mm [1 year-post]−1.00 [−4.00, 2.77]−1.20 [−5.15, 3.12]0.00 [−3.00, 3.20]*0.045

Values are median [interquartile range; Q1, Q3].

*P < 0.05 and **P < 0.001 compared to HG-AS.

Abbreviations are shown in Table 1.

Serial changes of LV remodelling patterns in each group

Figure 3 shows serial changes in the LV remodelling pattern in the three groups. The HG-AS group had a higher proportion of concentric hypertrophy than the other two groups at baseline (HG-AS 68.6% vs. cLFLG-AS 43.4% vs. pLFLG-AS 44.3%). At the 1-year follow-up, the proportion of the concentric hypertrophy pattern decreased in all groups, and the normal pattern was similar in all groups (HG-AS 13.6% vs. cLFLG-AS 13.7% vs. pLFLG-AS 15.1%). Notably, cLFLG-AS and pLFLG-AS had significantly higher rates of eccentric hypertrophy and concentric remodelling at baseline and 1 year post-TAVI than the other two groups; however, in pLFLG-AS, the fraction of concentric remodelling was almost unchanged during the 1 year following TAVI.

Serial cardiac remodelling pattern during 1 year in three groups. A) HG-AS, B) cLFLG-AS, and C) pLFLG-AS. Cardiac remodelling pattern: normal, concentric remodelling, eccentric remodelling, and concentric hypertrophy. cLFLG-AS, classical low-flow low-gradient aortic stenosis; HG-AS, high gradient aortic stenosis; LV, left ventricular; pLFLG-AS, paradoxical low-flow low-gradient aortic stenosis; RWT, relative wall thickness.
Figure 3

Serial cardiac remodelling pattern during 1 year in three groups. A) HG-AS, B) cLFLG-AS, and C) pLFLG-AS. Cardiac remodelling pattern: normal, concentric remodelling, eccentric remodelling, and concentric hypertrophy. cLFLG-AS, classical low-flow low-gradient aortic stenosis; HG-AS, high gradient aortic stenosis; LV, left ventricular; pLFLG-AS, paradoxical low-flow low-gradient aortic stenosis; RWT, relative wall thickness.

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PPM and PVR in both types of LFLG-AS compared with HG-AS

Regarding the rates of PPM ≥moderate and PVR ≥moderate, cLFLG-AS and pLFLG-AS had no significant differences in both indices compared with HG-AS at 1-year follow-up (PPM: cLFLG-AS vs. HG-AS, P = 0.927; pLFLG-AS vs. HG-AS, P = 0.148 and PVR: cLFLG-AS vs. HG-AS, P = 0.184; pLFLG-AS vs. HG-AS, P = 0.195; see Supplementary data online, Figure S5).

Discussion

In the present study, we aimed to investigate the clinical and echocardiographic outcomes after TAVI in symptomatic patients with cLFLG-AS and pLFLG-AS compared with those in patients with HG-AS. The main findings of this study are summarized as follows:

  1. cLFLG-AS and pLFLG-AS had worse 2-year adverse events compared with HG-AS, even after adjusting for clinical factors, underlying worse symptoms through a 2-year follow-up.

  2. In terms of aortic valve hemodynamics during 1-year follow-up after TAVI, HG-AS achieved continuous improvement, and both types of LFLG-AS maintained post-procedure improvement.

  3. One year after discharge, compared with HG-AS, TAVI for cLFLG-AS could provide a greater reduction in LV dimensions, greater increase in LVEF, and comparable LV mass regression, whereas pLFLG-AS could not receive more benefit from TAVI on the echocardiographic parameters.

Difference in baseline characteristics

The prevalence of HG-AS and both types of LFLG-AS may depend on the criteria used for stratification. According to a study using the same criteria, cLFLG-AS and pLFLG-AS were found in 19.6% and 9.9% of patients, respectively.7 The incidence rate of cLFLG-AS is significantly higher than that in this cohort because there were probably several patients with CAD in the overall population in their publication (prior MI, 5.5%; prior PCI, 22.4%; prior CABG, 4.3% vs. 69.5%).7 The low-flow state is predominantly caused by impaired LV systolic dysfunction, the most frequent cause being coronary ischaemia.17,18

This study highlights the differences in the background characteristics between HG-AS and both types of LFLG-AS. In summary, compared with HG-AS, cLFLG-AS included a higher number of male patients with worse HF symptoms, CFS and STS scores, and significantly more prior CVD events and was characterized by an eccentric remodelling pattern on echocardiography. In contrast, pLFLG-AS also had a higher number of male patients with more prior CVD events, especially AF, and was characterized by concentric remodelling patterns on echocardiography. Similar to previous publications, the cLFLG-AS group had the highest prevalence of CAD and STS scores, whereas the pLFLG-AS group had the highest prevalence of AF.5,7,11 This study included a large number of male patients in all three groups, which may be explained by ethnic differences.

Difference in procedural and clinical outcomes

Similar to previous reports, post-procedural aortic valve hemodynamics evaluated with TTE demonstrated marked relief from strong afterload and a large increase in AVA in all groups.5,8,10,17,19 In this study, a few differences in procedural complications were observed between both types of LFLG-AS and HG-AS. Compared with HG-AS, cLFLG-AS had a higher number of ischaemic strokes and fewer new PMIs, whereas pLFLG-AS had a higher number of new PMIs. As baseline risk factors for early cerebrovascular events following TAVI, female sex, chronic kidney disease, prior cerebrovascular events, and new-onset AF have been identified in previous studies and meta-analyses.20,21 However, cLFLG-AS in this cohort did not have more predictors than in the other two groups. They are derived from the post-TAVI results for the general AS population; thus, they may not fit in the TAVI for both types of LFLG-AS population because they are different from the general HG-AS population. Overall, there were no significant differences in the prevalence of other complications between HG-AS and each type of LFLG-AS; therefore, TAVI for both types of LFLG-AS is feasible and safe.

According to several previous reports on the clinical outcomes after TAVI in cLFLG-AS and pLFLG-AS compared with HG-AS, inconsistent results have been observed, especially when comparing pLFLG-AS and HG-AS.5,7,8,10–13 In studies using propensity score matching, TAVI for cLFLG-AS offered significantly worse 1-year mortality than HG-AS,13 whereas pLFLG-AS showed mortality comparable to HG-AS.8,13 There are some potential reasons for this discrepancy in results, one of which is that the quality of data in the studies does not allow a direct comparison of outcomes between LFLG-AS and HG-AS.8 Furthermore, treatment of HG-AS is a key determinant of prognosis, whereas in LFLG-AS, baseline comorbidities and other potential confounders lead to worse clinical outcomes.5 Previous reports have described that low-flow status is an important predictor of all-cause mortality in severe AS with preserved LVEF receiving medical and SAVR or TAVI,22,23 which can substantiate the findings in comparison between pLFLG-AS and HG-AS in the present study. Interestingly, in this study, after adjusting for major clinical factors that might influence outcomes, adverse event rates were comparable between cLFLG-AS and pLFLG-AS. In cLFLG-AS, possibly, the greater improvement in post-procedural echocardiographic parameters might be offset by worse baseline characteristics.

Patients with severe LV dysfunction derive greater health status benefits from TAVI than those with preserved LV function.19,24 In the current study, regarding HF symptoms based on the NYHA, both types of LFLG-AS had worse NYHA class at both baseline and follow-up than HG-AS. This may be explained by the fact that both types of LFLG-AS includes a greater number of patients with COPD, which means that it cannot strictly distinguish cardiac dyspnoea from lung dyspnoea.8 Nevertheless, there is no doubt about the efficacy of TAVI for both types of LFLG-AS, given the significantly lower fraction of NYHA Class III or IV at follow-up than at baseline.

Difference in serial echocardiographic parameters and remodelling patterns

In patients with severe AS, LVEF is often preserved and LV hypertrophy (LVH) develops gradually to reduce wall stress and maintain cardiac output.25 In general, in severe AS with moderate or severe LVH, relief of pressure overload with valve replacement is the largest trigger for LV mass regression, and greater regression of LV mass at 1 year is associated with lower mortality and rehospitalization for up to 5 years.26 However, limited to patients with LFLG-AS, there are remarkably few reports on the subsequent changes in cardiac structures and functions following TAVI. In a comparison between cLFLG-AS and HG-AS, from a study merging three clinical trials in patients treated with a self-expandable valve, at 1-year examination, cLFLG-AS showed no significant difference in AVA and a significantly lower pressure gradient.10 Improvement of aortic valve hemodynamics following TAVI for cLFLG-AS has been reported in previous studies,5,11,17,19 similar to the current study. In contrast, there were no statistically significant differences in MPG, LVEF, and PVR at 1-year examination.8 They also compared the interval changes in other echocardiographic parameters, including left chambers and SVi, in patients with pLFLG-AS; however, the interval time may be significantly short to sufficiently evaluate it (within 30 days).8 Thus, this study can provide a large contribution to understanding the differences in the pathophysiology between each type of LFLG-AS and HG-AS.

Myocardial fibrosis measured by extra cellular volume and late gadolinium enhancement with cardiac magnetic resonance was higher in cLFLG-AS, compared with HG-AS and pLFLG-AS.27,28 That is, because of more myocardial fibrosis in cLFLG-AS, it may be somehow surprising that even cLFLG-AS could obtain decent LV reverse remodelling including the reduction in LV dimensions and LV mass and the increase in LVEF at 1 year post-TAVI. This group did not have better 2-year clinical outcomes even after adjusting for confounders, in spite of the better effect on cardiac structure and function compared with HG-AS. The reason for that is assumed to be differences in status or comorbidities at baseline, such as worse CFS status and a greater number of prior CVD and COPD. Regarding LVEF recovery, patients with LFLG-AS with severely depressed LVEF at baseline derive greater benefits in terms of increased LVEF compared with patients with mildly depressed LVEF.19 Therefore, patients with a lower LVEF at baseline may be able to receive a greater increase in LVEF following relief from a strong afterload with TAVI.

There were no significant associations of adverse events with LV geometry at baseline after adjustment with confounders. This result is consistent with the previously large-scale report,29 and TAVI is likely to benefit patients with severe AS regardless of the presence of LVH.29 Moreover, the present study demonstrated that there might also be no impact of LV geometry at baseline on clinical outcomes in each type of flow-gradient pattern, except for eccentric hypertrophy in pLFLG-AS. On the other hand, this study also revealed the serial changes of LV geometry post-TAVI in each type of flow-gradient pattern, and further studies are needed to evaluate the impact of LV geometry post-TAVI on long-term clinical outcomes according to flow-gradient patterns.

This study did not consider factors that could lead to resistant LV reverse remodelling following TAVI. For example, transthyretin-related cardiac amyloidosis (ATTR-CA) may coexist in up to 16% of elderly TAVI candidates, and its presence can cause poor LV reverse remodelling after TAVI.30 The patients with pLFLG-AS included in this study might have had ATTR-CA, resulting in poorer regression of LV mass than in HG-AS. Predictors such as this are important when considering the subsequent changes in cardiac function or structure; however, the current study aimed to elucidate the differences in cardiac response following TAVI according to the flow gradient status in general clinical practice.

Limitations

This study has some limitations. First, this was a retrospective analysis based on a prospective multicenter TAVI cohort registry. Secondly, the echocardiographic data were not analysed by a centered core laboratory. Nevertheless, a small number of experienced echocardiographic physicians or technicians measured the echocardiographic images of all patients at every site. Thirdly, cardiac function and structure were evaluated using echocardiography, and were not examined using other tools, such as magnetic resonance imaging or computed tomography (CT). Moreover, we had no data on calcium score using CT. Fourthly, detailed information on the medical therapy after TAVI was not available for this analysis. Fifthly, data on DSE and/or non-contrast CT examination of aortic valve calcification, which are diagnostic tools used to confirm AS severity in patients with LFLG-AS, were not collected. Sixthly, there were differences in patients’ number among groups, thus the statistics used might not completely compensate for that. However, because of the difference of pathophysiology among groups, we considered that it made no sense to match the baseline characteristics using propensity score. Finally, this study did not consider transcatheter heart valve type or generation in depth, which may have affected the results.

Conclusion

In this large multicenter registry, TAVI for LFLG-AS is feasible and safe with a high improvement in aortic valve hemodynamics and similar rates of in-hospital complications as HG-AS. However, patients with LFLG-AS have more severe 2-year adverse events and underlying worse symptoms. During 1 year post-TAVI, compared with HG-AS, cLFLG-AS achieves smaller LV diameters, greater increase in LVEF, and comparable regression of LVMi, whereas pLFLG-AS does not.

Supplementary data

Supplementary data are available at European Heart Journal - Cardiovascular Imaging online.

Acknowledgements

The authors thank all the investigators and institutions for collecting the data, and the Japan Society of Clinical Research for their dedicated support for study completion.

Funding

The OCEAN-TAVI registry is supported by Edwards Lifesciences, Medtronic Japan, Boston Scientific, Abbott Japan, and Daiichi-Sankyo company.

Data availability

The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in this registry.

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Author notes

Conflict of interest: Dr Izumo is a screening proctor for Edwards Lifesciences. Dr Yashima, Dr Ohno, and Dr Asami are clinical proctors for Medtronic. Dr Takagi, Dr Naganuma, Dr Mizutani, and Dr Ueno are clinical proctors for Edwards Lifesciences and Medtronic. Dr Yamamoto, Dr Shirai, Dr Tada, Dr Watanabe, and Dr Hayashida, are clinical proctors for Edwards Lifesciences, Abbott Medical, and Medtronic. The remaining authors have nothing to disclose.

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