Cerebral ischemic injury after transcatheter aortic valve replacement in patients with pure aortic regurgitation 经导管主动脉瓣置换术治疗单纯主动脉瓣反流患者术后脑损伤 1 2 equal first-author https://orcid.org/0000-0003-1556-9198 1 2 equal 1 1 2 1 2 1 2 1 2 1 2 1 1 2 corresp equal Jian’an WANG, wangjianan111@zju.edu.cn Jian’an WANG, wangjianan111@zju.edu.cn wangjianan111@zju.edu.cn https://orcid.org/0000-0002-4583-3204 浙江大学医学院第二附属医院心内科， 中国杭州市， 310009 浙江大学医学院第二附属医院心内科， 中国杭州市， 310009 Department of Cardiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China Department of Cardiology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China 浙江大学医学院附属医学院内科学， 中国杭州市， 310058 浙江大学医学院附属医学院内科学， 中国杭州市， 310058 Internal Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China Internal Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China 目的 本研究旨在比较重度主动脉瓣狭窄（AS）和单纯主动脉瓣反流（AR）患者接受经导管主动脉瓣置换术（TAVR）后发生脑损伤的风险。 方法 回顾性分析287例AS和65例单纯AR接受TAVR的患者。患者在TAVR术前和术后3天进行头颅磁共振检查。 结果 本研究中57.7%为男性；单纯AR患者年龄较小（71岁vs.74岁； P =0.001），美国心胸外科医师协会评分较低（2.39 vs. 3.89； P < 0.001）；3.1%的患者在出院前发生了症状性脑卒中；单纯AR组脑损伤病灶发生率（83.1% vs. 85.0%； P =0.695），病灶数（3.0 (1.5‒7.5) vs. 3.0 (1.0‒8.0)； P =0.928)和总体积（130.0 mm³ vs. 190.0 mm 3 ； P =0.585）与AS组相比差异无统计学意义；此外，单纯AR组中的经股动脉入路和经心尖入路相比，无论是病灶数（3.0 (2.0‒7.0) vs. 3.5 (1.0‒8.3)； P =0.923）还是总体积（120.0 mm 3 vs. 135.0 mm 3 ； P =0.837）均相似。多元广义泊松回归模型证实吸烟史、慢性肾脏病4期或5期、左室流出道钙化是单纯AR患者TAVR术后脑损伤病灶数的独立预测因素。 结论 AS组与单纯AR组相比，TAVR术后新发脑损伤病灶的发生率、数量及总体积差异均无统计学意义。 脑损伤 经导管主动脉瓣置换术 单纯主动脉瓣反流 经股动脉入路 经心尖入路 Considering the surgical risk stratification for patients with severe calcific aortic stenosis (AS), transcatheter aortic valve replacement (TAVR) is a reliable alternative to surgical aortic valve replacement (SAVR) ( Fan et al., 2020 Fan et al., 2020 , 2021 2021 ; Lee et al., 2021 Lee et al., 2021 ). Despite the favorable clinical benefits of TAVR, stroke remains a dreaded perioperative complication ( Auffret et al., 2016 Auffret et al., 2016 ; Kapadia et al., 2016 Kapadia et al., 2016 ; Kleiman et al., 2016 Kleiman et al., 2016 ; Huded et al., 2019 Huded et al., 2019 ). Ischemic overt stroke, identified in 1.4% to 4.3% of patients in TAVR clinical practice, has been associated with prolonged disability and increased mortality ( Auffret et al., 2016 Auffret et al., 2016 ; Kapadia et al., 2016 Kapadia et al., 2016 ; Levi et al., 2022 Levi et al., 2022 ). The prevalence of hyperintensity cerebral ischemic lesions detected by diffusion-weighted magnetic resonance imaging (DW-MRI) was reported to be about 80%, which is associated with impaired neurocognitive function and vascular dementia ( Vermeer et al., 2003 Vermeer et al., 2003 ; Barber et al., 2008 Barber et al., 2008 ; Kahlert et al., 2010 Kahlert et al., 2010 ). SAVR is usually recommended for patients with severe pure aortic regurgitation (AR) who require surgery for other indications, with impaired left ventricular systolic function (≤50%) or left ventricular enlargement ( Otto et al., 2021 Otto et al., 2021 ). However, a considerable proportion of pure AR patients cannot tolerate SAVR because of the heavy burden of clinical comorbidities. Likewise, prior studies reported that the performance of TAVR in AS patients is superior or non-inferior to that in pure AR patients ( Testa et al., 2014 Testa et al., 2014 ; Shi et al., 2021 Shi et al., 2021 ). Pure AR has been considered as a relative contraindication for TAVR due to the increased risk of prosthetic valve dislodgement in the absence of aortic valve calcification ( Seiffert et al., 2013 Seiffert et al., 2013 ; Sawaya et al., 2017 Sawaya et al., 2017 ). With the further accumulation of operator experience and the advancement of devices over the past few decades, the continuous “off-label” use of TAVR in pure AR patients has become the subject of intense research ( Hira et al., 2017 Hira et al., 2017 ; Alharbi et al., 2020 Alharbi et al., 2020 ). JenaValve (JenaValve Technology, Inc., Irvine, CA, USA) and J-Valve (Suzhou Jiecheng Medical Technology Co., Ltd., Suzhou, China), which feature anchoring by grasping native leaflets, have been commercially approved for the treatment of non-calcified aortic valvular disease. However, the characteristics of cerebral ischemic lesions in pure AR patients remain unclear ( Yoon et al., 2017 Yoon et al., 2017 ; Stachon et al., 2020 Stachon et al., 2020 ). Herein, we aimed to compare the differences in cerebral ischemic lesions between AS and pure AR, as well as explore the detailed characteristics of these lesions in pure AR patients. A total of 352 patients who underwent TAVR participated in this study. Of these, 287 patients underwent TAVR for AS and 65 for pure AR. The baseline, echocardiographic, and multi-detector computed tomography (MDCT) data of patients are described in Table 1 Table 1 . More than half of the entire study population were male. Pure AR patients were younger (71 (64.5–75.0) years vs. 74.0 (69.0–79.0) years; P =0.002) and had lower Society of Thoracic Surgeons (STS) scores (2.39 (1.48–4.21) vs. 3.89 (2.33–6.39); P < 0.001) compared with AS patients. AS patients had a higher prevalence of diabetes mellitus and chronic obstructive pulmonary disease, but a lower prevalence of hypertension and atrial fibrillation. New York Heart Association (NYHA) functional class III/IV was presented in 78.4% of AS patients and 66.2% of pure AR patients at admission. Values are expressed as median (IQR), number (percentage), or mean±SD. AS: aortic stenosis; AR: aortic regurgitation; STS: Society of Thoracic Surgeons; NYHA: New York Heart Association; COPD: chronic obstructive pulmonary disease; CKD: chronic kidney disease; PVD: peripheral vascular disease; EF: ejection fraction; LVEDD: left ventricular end-diastolic diameter; AVA: aortic valve area; MR: mitral regurgitation; TR: tricuspid regurgitation; MDCT: multi-detector computed tomography; STJ: sinotubular junction; LM: left main artery; RCA: right coronary artery; SD: standard deviation; IQR: interquartile range; 1 mmHg=133.322 Pa. Characteristics Global ( n =352) AS ( n =287) Pure AR ( n =65) P value Baseline Age (years) 73.0 (68.0‒78.0) 74.0 (69.0‒79.0) 71.0 (64.5‒75.0) 0.001 Male 203 (57.7%) 162 (56.4%) 41 (63.1%) 0.329 STS (%) 3.49 (2.11‒5.93) 3.89 (2.33‒6.39) 2.39 (1.48‒4.21) <0.001 NYHA III/IV 268 (76.1%) 225 (78.4%) 43 (66.2%) 0.037 Smoker 77 (21.9%) 60 (20.9%) 17 (26.2%) 0.355 Hypertension 200 (56.8%) 155 (54.0%) 45 (69.2%) 0.025 Diabetes 68 (19.3%) 65 (22.6%) 3 (4.6%) 0.001 Atrial fibrillation 57 (12.8%) 43 (15.0%) 14 (21.5%) <0.001 Prior stroke 13 (3.7%) 9 (3.1%) 4 (6.2%) 0.423 COPD 71 (20.2%) 64 (22.3%) 7 (10.8%) 0.036 CKD 4/5 33 (9.4%) 27 (9.4%) 6 (9.2%) 0.965 PVD 25 (7.1%) 19 (6.6%) 6 (9.2%) 0.637 Echocardiography data EF (%) 60.0 (47.2‒64.6) 60.2 (48.8‒64.6) 56.9 (44.5‒64.8) 0.186 LVEDD (cm) 4.92 (4.32‒5.67) 4.69 (4.23‒5.34) 5.95 (5.32‒6.64) <0.001 Max velocity (m/s) 4.56 (4.11‒5.21) 4.74 (4.33‒5.37) 1.97 (1.75‒2.23) <0.001 Mean gradient (mmHg) 48.0 (38.0‒64.0) 52.0 (42.0‒67.0) 8.0 (6.0‒10.0) <0.001 AVA (cm²) 0.65 (0.50‒0.81) 0.62 (0.47‒0.77) 2.03 (1.74‒2.43) <0.001 ≥Moderate MR 98 (27.8%) 73 (25.4%) 25 (38.5%) 0.034 ≥Moderate TR 45 (12.8%) 36 (12.5%) 9 (13.8%) 0.776 MDCT data Perimeter (mm) 77.5 (72.3‒83.5) 76.5 (72.0‒82.7) 82.2 (76.0‒88.5) <0.001 STJ diameter (mm) 31.5±4.7 30.6±4.0 35.5±5.6 <0.001 STJ height (mm) 21.8 (19.2‒25.1) 21.3 (19.0‒24.1) 25.2 (21.8‒29.6) <0.001 Ascent aortic diameter at 4 cm (mm) 37.7 (34.8‒41.0) 37.5 (34.4‒40.7) 38.3 (35.6‒41.5) 0.081 LM height (mm) 14.3 (12.1‒17.0) 14.3 (12.2‒16.8) 14.3 (11.7‒17.8) 0.877 RCA height (mm) 16.7 (14.7‒18.8) 16.6 (14.5‒18.6) 17.7 (15.5‒21.2) 0.003 Aortic root angle (°) 51.0 (45.0‒59.0) 51.0 (46.0‒57.0) 56.0 (46.0‒61.5) 0.011 In terms of echocardiography, the overall median left ventricle ejection fraction (LVEF) was 60.0%. Pure AR patients showed a more pronounced cardiac dilatation with larger left ventricle diastolic diameters (5.95 (5.32‍–6.64) cm vs. 4.69 (4.23–5.34) cm; P ˂0.001). Larger aortic valve area (2.03 (1.74–2.43) cm² vs. 0.62 (0.47‍–0.77) cm²; P ˂0.001) and moderate or severe mitral regurgitation (38.5% vs. 25.4%; P =0.034) were more frequently observed in these patients. The dimensions of Valsalva sinuses in pure AR patients were larger, which was manifested not only in the perimeter of annulus area but also in the perimeter of sinotubular junctions ((35.5±5.6) mm vs. (30.6±4.0) mm; P < 0.001). Likewise, aortic root dilatation was more significant in pure AR patients. There were no differences between the two groups in the left main coronary artery ostium height, but the right coronary artery ostium height was significantly higher (17.7 (15.5–21.2) mm vs. 16.6 (14.5–18.6) mm; P =0.003) in pure AR patients. All patients were implanted with the self-expanding valves. Table 2 Table 2 shows the periprocedural characteristics. Pre-dilatation (99.0% vs. 0%, P < 0.001) and post-dilatation (69.7% vs. 13.8%, P < 0.001) were applied more often in the AS group. Pure AR patients had longer hospital stay than AS patients ( P < 0.001). The incidence of peri-procedural complications did not differ significantly between the two groups. All patients survived except one who died of myocardial infarction before discharge. Symptomatic stroke occurred in 3.1% of patients before discharge. Three AS patients had disabling stroke, whereas non-disabling stroke occurred in six AS patients and two pure AR patients. The incidence of new-onset atrial fibrillation in the pure AR group was significantly higher than that in AS patients (16.9% vs. 3.1%, P < 0.001), which may contribute to the higher proportion of anticoagulation regimens (41.5% vs. 18.5%, P < 0.001). All data are presented as number (percentage) or median (IQR). AS: aortic stenosis; AR: aortic regurgitation; TAVR: transcatheter aortic valve replacement; MACE: major adverse cardiovascular event; MI: myocardial infarction; PVL: perivalvular leakage; PPM: patient-prosthesis mismatch; IQR: interquartile range. Characteristics Global ( n =352) AS ( n =287) Pure AR ( n =65) P value Procedural characteristics Pre-dilatation 284 (80.7%) 284 (99.0%) 0 <0.001 Post-dilatation 209 (59.4%) 200 (69.7%) 9 (13.8%) <0.001 Annular rupture 2 (0.6%) 1 (0.3%) 1 (1.5%) 0.336 Coronary obstruction 1 (0.3%) 1 (0.3%) 0 1.000 Aortic dissection 3 (0.9%) 3 (1.0%) 0 0.936 Second valve implantation 31 (8.8%) 25 (8.7%) 6 (9.2%) 0.894 Outcomes before discharge Post TAVR hospital stay (d) 5.0 (1.0‒7.0) 3.0 (1.0‒7.0) 8.0 (6.0‒9.0) <0.001 MACE 12 (3.4%) 10 (3.5%) 2 (3.1%) 1.000 Mortality 1 (0.3%) 1 (0.3%) 0 1.000 Stroke 11 (3.1%) 9 (3.1%) 2 (3.1%) 1.000 Disabling stroke 3 (0.9%) 3 (1.0%) 0 1.000 Non-disabling stroke 8 (2.3%) 6 (2.1%) 2 (3.1%) 0.983 MI 1 (0.3%) 1 (0.3%) 0 1.000 ≥Moderate PVL 18 (5.1%) 17 (5.9%) 1 (1.5%) 0.255 New-onset atrial fibrillation 20 (5.7%) 9 (3.1%) 11 (16.9%) <0.001 Pacemaker implantation 10 (2.8%) 8 (2.8%) 2 (3.1%) 1.000 Severe PPM 16 (4.6%) 15 (5.3%) 1 (1.6%) 0.362 Medication <0.001 Anticoagulation 80 (22.8%) 53 (18.5%) 27 (41.5%) Antiplatelet 280 (79.5%) 241 (84.0%) 39 (60.0%) No antithrombosis 5 (1.4%) 5 (1.7%) 0 DW-MRI was performed at a median of 3.0 d after TAVR. A total of 1981 new cerebral ischemic lesions were recognized on post-procedural DW-MRI in 298 patients (84.7%), with a median of 3.0 (interquartile range (IQR): 1.0–8.0) lesions per patient ( Table 3 Table 3 ). Most patients (87.2%), regardless of AS or pure AR, had multiple cerebral ischemic lesions, scattered in the bilateral cerebral hemispheres and cerebrovascular territories ( Table 3 Table 3 , Fig. S1). About 86.0% of patients had a total cerebral ischemic lesion volume of < 1000 mm 3 . There was no significant difference in the rate (85.0% vs. 83.1%; P =0.695) or number (3.0 (1.0‍–8.0) vs. 3.0 (1.5‍–‍7.5); P =0.928) of ischemic lesions between the two groups ( Table 3 Table 3 , Fig. S1). The number of lesions counted in any cerebral region was comparable between the two groups ( Fig. 1 Fig. 1 ). The median volume of ischemic lesion was 190.0 mm³ in the AS group and 130.0 mm³ in the pure AR group ( P =0.585; Table 3 Table 3 , Fig. S1). All data are presented as median (IQR), number (percentage), or number for skewed variables. DW-MRI: diffusion-weighted magnetic resonance imaging; TAVR: transcatheter aortic valve replacement; AS: aortic stenosis; AR: aortic regurgitation; ACA: anterior cerebral artery; MCA: middle cerebral artery; PCA: posterior cerebral artery; VA: vertebral artery; BA: basilar artery; IQR: interquartile range. Characteristics Global ( n =352) AS ( n =287) Pure AR ( n =65) P value MRI after TAVR (d) 3.0 (1.0‒5.0) 2.0 (1.0‒4.0) 5.0 (4.0‒6.0) <0.001 Patients with new lesions 298 (84.7%) 244 (85.0%) 54 (83.1%) 0.695 Total new lesions 1981 1618 363 New lesions per patients 3.0 (1.0‒8.0) 3.0 (1.0‒8.0) 3.0 (1.5‒7.5) 0.928 Patients with a single lesion 38 (12.8%) 33 (13.5%) 5 (9.3%) 0.395 Patients with multiple lesions 260 (87.2%) 211 (86.5%) 49 (90.7%) Patients with bi-hemispheric lesions 196 (55.7%) 162 (56.4%) 34 (52.3%) 0.544 Lesion location ACA 99 (28.1%) 83 (28.9%) 16 (24.6%) 0.486 ACA/MCA 80 (22.7%) 63 (21.9%) 17 (26.2%) 0.465 MCA 190 (54.0%) 151 (52.6%) 39 (60.0%) 0.281 MCA/PCA 47 (13.4%) 37 (13.4%) 10 (15.4%) 0.594 PCA 171 (48.6%) 140 (48.8%) 31 (47.7%) 0.874 VA/BA 184 (52.3%) 153 (53.3%) 31 (47.7%) 0.413 Lesion volume (mm 3 ) 55.0 (26.7‒88.3) 56.0 (30.0‒87.8) 46.7 (15.0‒91.3) 0.252 Maximal lesion volume per patient (mm 3 ) 90.0 (40.0‒190.0) 90.0 (40.0‒190.0) 70.0 (20.0‒185.0) 0.320 Total lesion volume per patient (mm 3 ) 180.0 (60.0‒587.5) 190.0 (60.0‒570.0) 130.0 (40.0‒715.0) 0.585 Patients with total lesion volume of ≥1000 mm 3 50 (14.2%) 39 (13.6%) 11 (16.9%) 0.487 Concerning transfemoral (TF)- or transapical (TA)-TAVR, both the number of lesions per patient (3.0 (2.0‍–‍7.0) vs. 3.5 (1.0–8.3); P =0.923) and the total lesion volume per patient (120.0 (50.0‍–‍650.0) mm 3 vs. 135.0 (35.0‍–‍745.0) mm 3 , P =0.837) were comparable (Table S1). There were no significant differences in the lesions counts in all cerebral regions except the middle cerebral artery (MCA) and the area between MCA and posterior cerebral artery (MCA/PCA) regions; there were more numerous lesions in MCA region after TF-TAVR and more lesions in MCA/PCA region after TA-TAVR. As listed in Table 4 Table 4 , Poisson regression analysis was used to explore baseline risk factors related to the number of ischemic lesions by DW-MRI in the pure AR group. The univariate variables (smoking history, diabetes, cancer, Stage 4 or 5 chronic kidney disease (CKD 4/5), moderate or greater tricuspid regurgitation, and calcification of left ventricular outflow tract (LVOT)) with a P ˂0.10 were subsequently entered into a multivariate Poisson regression model. Finally, the multivariable regression model confirmed that smoking history, CKD 4/5, and the calcification of LVOT were independent risk factors associated with the increased number of cerebral ischemic lesions in pure AR patients. Univariate analysis was included in the multivariate Poisson regression analysis model. SE: standard error; AR: aortic regurgitation; STS: the Society of Thoracic Surgeons; CKD: chronic kidney disease; PVD: peripheral vascular disease; EF: ejection fraction; MR: mitral regurgitation; TR: tricuspid regurgitation; LVOT: left ventricular outflow tract; HU: Hounsfield units. 2 Characteristics 2 Univariate Poisson regression 2 Multivariate Poisson regression Β (SE) P value Β (SE) P value Age 0.014 0.315 Male -0.246 0.348 STS 0.009 0.770 Smoker -0.687 0.011 -0.672 0.015 Hypertension -0.088 0.776 Diabetes -0.692 0.088 -0.454 0.184 Atrial fibrillation 0.268 0.379 Cancer -0.866 <0.001 -0.388 0.108 CKD 4/5 -0.889 0.001 -0.751 0.020 PVD -0.225 0.454 Prior stroke 0.839 0.155 Medication on admission Antiplatelet -0.229 0.422 Anticoagulation 0.412 0.211 EF (%) -0.002 0.873 ≥Moderate MR 0.126 0.633 ≥Moderate TR 0.820 0.015 0.402 0.164 Calcification of annulus 0.426 0.514 Calcification of leaflets 0.428 0.230 Calcification of LVOT 0.471 0.001 0.810 <0.001 Calcification of aorta 0.074 0.785 Calcium score 650 HU 0.000 0.124 850 HU 0.000 0.422 HU+100 0.000 0.940 Our data showed a high prevalence (84.7%) of ischemic lesions. To the best of our knowledge, this is the first study to demonstrate that cerebral ischemic lesions are comparable between AS patients and pure AR patients after TAVR; the same was found regarding the comparison between TA- with TF-TAVR in the pure AR subgroup. Moreover, smoking history, CKD 4/5, and calcification of the LVOT were independently associated with the number of ischemic lesions in the pure AR population. AR is prevalent with an estimated incidence of moderate and severe AR up to 0.5% ( Maurer, 2006 Maurer, 2006 ). However, a considerable number of high-risk patients are not referred to receiving SAVR due to multiple existing commodities ( Iung et al., 2003 Iung et al., 2003 ). Considering the technical challenges of prothesis valve anchoring and sealing, pure AR has been regarded as one of the exclusion criteria in most well-designed trials of TAVR. Some studies have reported the early safety and feasibility of TAVR in pure AR ( Roy et al., 2013 Roy et al., 2013 ; Yoon et al., 2017 Yoon et al., 2017 ). Second-generation “on-label” devices, such as JenaValve and J-Valve, are equipped with anchoring elements specifically designed for non-calcific pure AR ( Schäfer et al., 2017 Schäfer et al., 2017 ; Hensey et al., 2019 Hensey et al., 2019 ). In our study, the incidence of major adverse cardiovascular event (MACE) was comparable between AS and pure AR populations, suggesting that pure AR patients could benefit greatly from TAVR. However, pure AR patients tended to have longer hospital stays, which may be due to the higher proportion of the TA approach. The newer-generation JenaValve and J-Valve systems via the TF approach have proved to be associated with favorable outcomes in patients with noncalcified aortic valve disease ( Schäfer et al., 2017 Schäfer et al., 2017 ; Hensey et al., 2019 Hensey et al., 2019 ). Undoubtedly, the etiology of periprocedural stroke is linked to a combination of multiple factors and varies from the timing of stroke. Within the first 2 d after TAVR, as demonstrated by transcranial Doppler ultrasound during the TAVR period ( Kahlert et al., 2012 Kahlert et al., 2012 ), catheter manipulation within the diseased native annulus and aortic arch disrupts both the endothelial covering and the underlying friable calcific material, causing subsequent cardiogenic embolization ( Omran et al., 2003 Omran et al., 2003 ; Daneault et al., 2011 Daneault et al., 2011 ). Between 2 d to the first month after TAVR, factors strongly predicting early neurological events are likely to be linked to chronic hypotensive episodes ( Miller et al., 2012 Miller et al., 2012 ), such as patient comorbidities and clinical antibacterial drug application. Therefore, late stroke (more than 30 d after TAVR) seems to be dominantly related to patients’ own characteristics rather than the TAVR procedure ( Bosmans et al., 2015 Bosmans et al., 2015 ). Similarly, cerebral lesions were disseminated in bilateral cerebral hemispheres, suggesting that the essence of the lesions is cardioembolic. Embolized tissues were detached from the native aortic valve leaflets, aortic wall, left ventricular myocardium, and foreign material ( van Mieghem et al., 2015 van Mieghem et al., 2015 ; Kapadia et al., 2017 Kapadia et al., 2017 ). Differences reported in the incidence of stroke between the AS and the pure AR groups after TAVR are inconclusive. The German nationwide aortic valve replacement clinical practice shows that the incidence of stroke in pure AR patients after TF-TAVR was lower than that in AS patients (1.47% vs. 2.53%) ( Stachon et al., 2020 Stachon et al., 2020 ). A large-scale study based on the United States Nationwide Readmissions Database presented that the occurrence of stroke after TAVR in the pure AR group was comparable with the pure AS ( P =0.745) and AS+AR groups ( P =0.621) ( Isogai et al., 2021 Isogai et al., 2021 ). Previous studies have confirmed that age and the volume of aortic valve calcification are predictors of cerebral embolism after TAVR ( Fairbairn et al., 2012 Fairbairn et al., 2012 ; Samim et al., 2015 Samim et al., 2015 ). Balloon dilatation has been found to significantly increase the possibility of detachment of calcified particles ( Samim et al., 2015 Samim et al., 2015 ). However, in our study, the incidence of stroke did not appear to differ statistically between the AS and pure AR groups (3.1% vs. 3.1%; P =1.000), despite that AS patients were older, presented with more comorbidities, and had more severe aortic root calcification burden and more balloon pre- and post-dilatation. Consistent with pilot studies, the detection rate of cerebral ischemic foci on DW-MRI was 85.0% in the AS group and 83.1% in the pure AR group ( Ghanem et al., 2010 Ghanem et al., 2010 ; Kahlert et al., 2010 Kahlert et al., 2010 ). Likewise, no statistical differences were shown in the total number, volume, or distribution of ischemic lesions on DW-MRI between AS and pure AR patients. Yoon et al. (2017) Yoon et al. (2017) revealed a relatively high prevalence of stroke for next-generation devices (39.2% vs. 12.6%; P < 0.001). The authors hypothesized that this is probably due to the TA access and complex procedures applied. Similarly, Stachon et al. (2020) Stachon et al. (2020) showed a higher stroke rate in TA- than in TF-TAVR (2.82% vs. 1.47%). However, these findings were refuted by multiple registries that revealed no significant difference in symptomatic stroke or asymptomatic stroke between the TF and TA approaches ( Astarci et al., 2011 Astarci et al., 2011 ; Huded et al., 2019 Huded et al., 2019 ; Guo et al., 2021 Guo et al., 2021 ). A well-conducted meta-analysis published by Wernly et al. (2019) Wernly et al. (2019) summarized that symptomatic stroke occurred in 2.8% of patients with second-generation “on-label” devices and in 2.6% with other second-generation “off-label” devices. TF-TAVR involves excessive interaction with the aorta wall and retrograde crossing of the calcified aortic valve, which might contribute to the occurrence of dislodged particles ( Omran et al., 2003 Omran et al., 2003 ). However, TA-TAVR is more complicated and traumatic, which may involve a higher risk of air embolism due to the direct puncture of apex and could increase the risk of cerebral embolism ( Yoon et al., 2017 Yoon et al., 2017 ; Guo et al., 2021 Guo et al., 2021 ). The similar results of DW-MRI between the two approaches in pure AR also suggested the complexity of the mechanism of TAVR-related cerebral embolism ( Kahlert et al., 2012 Kahlert et al., 2012 ; Athappan et al., 2014 Athappan et al., 2014 ). With regard to baseline predictors, smoking history, higher creatinine level, and aortic valve plaque at the threshold of 50 to 130 Hounsfield units (HU) have been identified as predictors of ischemic injury in AS patients ( Kajio et al., 2019 Kajio et al., 2019 ). However, independent predictors of ischemic stroke in pure AR patients have not been explored in previous studies. Our findings demonstrated that smoking history, CKD 4/5, and calcification of LVOT were effective predictors in pure AR patients. Smoking history and CKD 4/5, widely considered as cardiovascular risk factors and linked with an increased atherosclerotic burden, have been noted to be independent predictors of stroke after TAVR by prior investigators ( Ambrose and Barua, 2004 Ambrose and Barua, 2004 ; Auffret et al., 2016 Auffret et al., 2016 ). The calcification of LVOT was identified by Pollari et al. (2020) Pollari et al. (2020) to contribute to an increasing risk of peri-procedural stroke and mortality. It is remarkable that calcification of LVOT was determined as one of the predictors of cerebral lesion in the pure AR population in our analysis, even though calcification around the aortic valve was scarce. Considering the small sample size of pure AR patients in our study and the complexity of the TAVR procedure, larger-scale studies are needed to establish a more reliable risk prediction model for cerebral ischemic injury. As widely known, new ischemic lesions detected on DW-MRI are related to cognitive decline and long-term dementia ( Vermeer et al., 2003 Vermeer et al., 2003 ; Barber et al., 2008 Barber et al., 2008 ; Kahlert et al., 2010 Kahlert et al., 2010 ). Although this has been studied extensively, a knowledge gap exists with regard to the pathogenesis of cognitive decline after cerebral ischemic injury. The following points have been established in this regard: (1) Cognitive function is a high-level functional activity coordinated by cerebral multiple functional regions and the nervous system. The ischemia-hypoxia injury in the cerebral eloquent area may lead to cognitive decline. (2) Cerebral atrophy, probably caused by ischemia-related cortical neurodegeneration, especially in the cortical and subcortical areas, can exacerbate cognitive decline ( Duering et al., 2012 Duering et al., 2012 ). (3) Cerebral ischemic injury may induce sustained inflammation, leading to secondary disorders of the internal environment and blood-brain barrier damage ( Kliper et al., 2013 Kliper et al., 2013 ). (4) There exists a complex interaction between cerebral ischemic injury and Alzheimer’s disease ( Hénon et al., 2001 Hénon et al., 2001 ). New-onset cerebral ischemic injury may accelerate the progression of Alzheimer’s disease and cerebral microvascular dysfunction. (5) Accumulating evidence shows that cognitive decline after stroke is an independent risk factor for vascular dementia ( Hénon et al., 2001 Hénon et al., 2001 ). In addition, there is proof that vascular abnormalities play a role in the development of dementia and cognitive dysfunction ( Barber et al., 2008 Barber et al., 2008 ). In our study, 85.0% of AS patients and 83.1% of the pure AR population had cerebral ischemic injury. Given that pure AR patients are usually younger than AS patients and the rate of cerebral ischemic lesions between two groups is similar, the risk of cerebral ischemic injury for pure AR patients undergoing TAVR cannot be ignored and attention must be paid to the safe peri-procedural management of these patients. Therefore, cerebral embolic protection devices might be recommended for pure AR patients scheduled for TAVR to reduce the incidence of stroke. The main limitations of our single-center observational study have been elaborated as follows: first, we found many differences in the baseline characteristics between the AS and pure AR groups, yet we did not explore the predictors of stroke in the total study population; second, our findings should be interpreted with caution because the number of patients in the two groups was not balanced due to the selection of patients in clinical practice; third, prosthesis valve selection is based on operator discretion rather than randomization; finally, this study cannot determine the exact mechanism of cerebral ischemic lesions. Long-term follow-up research should be considered to further evaluate the impact of ischemic lesions on cognitive function. Overall, cerebral ischemic lesions after TAVR were highly prevalent and no differences were found between pure AR patients and AS patients, which provides critical information for clinicians to help with patient management. 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All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. This work was supported by the Zhejiang Province Science and Technology Department Key R&D Program (No. 2021C03097), China. 10.1631/jzus.B2200444 1673-1581（2023）06-0530-09 刘先宝,戴晗怡,范嘉祺等.经导管主动脉瓣置换术治疗单纯主动脉瓣反流患者术后脑损伤[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(06):530-538. 刘先宝,戴晗怡,范嘉祺等.经导管主动脉瓣置换术治疗单纯主动脉瓣反流患者术后脑损伤[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2023,24(06):530-538. This work was supported by the Zhejiang Province Science and Technology Department Key R&D Program (No. 2021C03097), China. 2022-09-05 2023-01-20 2023-06-15 2023-07-04 Copyright © Zhejiang University and Springer-Verlag GmbH Germany, part of Springer Nature 2022 2023 浙江大学出版社 38646238 Xianbao LIU, Hanyi DAI, Jiaqi FAN, Dao ZHOU, Gangjie ZHU, Abuduwufuer YIDILISI, Jun CHEN, Yeming XU, Lihan WANG, and Jian'an WANG declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. The ethical approval institution is the Second Affiliated Hospital of Zhejiang University School of Medicine (No. 2014-159). Informed consent was obtained from the patient for being included in the report. Compliance with ethics guidelines Supplementary information 1 Materials and methods; Fig. S1; Table S1 浙江大学学报（英文版）（B辑：生物医学和生物技术） 6 24