Direct transcatheter aortic valve implantation (TAVI) decreases silent cerebral infarction when compared to routine balloon valvuloplasty

Purpose: Silent cerebral infarctions (SCI), as determined by neuron-specific enolase (NSE) elevations, may develop after the transcatheter aortic valve implantation (TAVI) procedure. Our aim in this study was to compare the SCI rates between patients who underwent routine pre-dilatation balloon aortic valvuloplasty (pre-BAV) and patients who underwent direct TAVI without pre-BAV. Methods: A total of 139 consecutive patients who underwent TAVI in a single center using the self-expandable Evolut-R valve (Medtronic, Minneapolis, Minnesota, USA) were included in the study. The first 70 patients were included in the pre-BAV group, and the last 69 patients were included in the direct TAVI group. SCI was detected by serum NSE measurements performed at baseline and 12 h after the TAVI. New NSE elevations > 12 ng/mL after the procedure were counted as SCI. In addition, SCI was scanned by MRI (magnetic resonance imaging) in eligible patients. Results: TAVI procedure was successful in all of the study population. Post-dilatation rates were higher in the direct TAVI group. Post-TAVI NSE positivity (SCI) was higher in the routine pre-BAV group (55(78.6%) vs. 43(62.3%) patients, p = 0.036) and NSE levels were also higher in this group (26.8 ± 15.0 vs. 20.5 ± 14.8 ng/ml, p = 0.015). SCI with MRI was found to be significantly higher in the pre-BAV group than direct TAVI group (39(55.1%) vs. 31(44.9%) patients). The presence of atrial fibrillation and diabetes mellitus (DM), total cusp calcification volume, calcification at arcus aorta, routine pre-BAV and failure at first try of the prosthetic valve implantation were significantly higher in SCI (+) group. In the multivariate analysis, presence of DM, total cusp calcification volume, calcification at arcus aorta, routine pre-BAV and failure at first try of the prosthetic valve implantation were significantly associated with new SCI development. Conclusions: Direct TAVI procedure without pre-dilation seems to be an effective method and avoidance of pre-dilation decreases the risk of SCI development in patients undergoing TAVI with a self-expandable valve.


Introduction
Transcatheter aortic valve implantation (TAVI) has become a standard procedure for the treatment of eligible patients with aortic stenosis.Balloon aortic valvuloplasty (BAV) was a standard procedure before TAVI to increase deliverability of the valve and diminish the counterforce of the calcific aortic valve.In years, with the improvement of the valve structure and delivery system, the profile of the TAVI system has become smaller and radial force of the selfexpandable valves increased, therefore routine BAV has started to be neglected in many patients undergoing TAVI with self-expandable valves.Besides, BAV is known to be associated with some complications including severe aortic regurgitation, annular rupture and hemodynamic instability due to rapid pacing in some patients [1][2][3][4] so direct TAVI without routine pre-BAV seems to be a good option for many patients.Furthermore, in randomised studies, the safety and efficacy of direct TAVI have been shown both for self and balloon expandable valves [5,6].
Aside from death, the most important complication of TAVI procedure is the increased stroke rate of 2-10% in randomised controlled studies especially in high-risk population decreasing in lower-risk patients (< 2%) [7-9] and 2.3% in a real-world registry [10].Besides, silent cerebral infarction (SCI) rate has been reported to be > 70% in a meta-analysis [11].The effects of SCI become important in these elder patients most of whom have mildly impaired neurological functions because SCI has been demonstrated to be related to some neurologic and psychiatric disorders and mortality [12][13][14][15][16]. Therefore, preventing embolic and ischemic events during TAVI is an important issue and some preventive measures including embolic filters have been studied but up to date none of them has been proven clinically effective [11].
In randomised studies comparing routine pre-dilation vs. direct TAVI [5,6], no difference has been observed between groups in terms of stroke, but SCI has never been studied.In this study, we aimed to compare SCI rates between patients who underwent TAVI with routine pre-BAV vs. direct TAVI without balloon pre-dilation.

Study procedure
This study was designed as an allocated, prospective, single centre study.After exclusion criteria were applied, a total number of 139 consecutive patients who underwent TAVI with a self-expandable Evolut-R (Medtronic, Minneapolis, Minnesota, USA) valve at a single centre between February 2019 and June 2022 were included in the study.To eliminate a possible bias about the operator's choice of TAVI procedure, we designed a sequential randomization.First 70 patients were enrolled to the routine pre-dilation (pre-BAV) group and the last 69 patients were included to direct-TAVI group without pre-dilation.The randomisation chart of the patients can be seen in Fig. 1.
Our study complies with the Declaration of Helsinki.All patients gave written informed consent and local ethics committee approved the study protocol (date: 02/27/2019, no: SBUSEAH-KAEK 2019/2/4).Clinical data, patient characteristics, laboratory data, echocardiography data, procedural variables, and details of the length of hospital stay were collected from hospital medical records.

Patient selection and exclusion criteria
Echocardiography was performed on all of the patients to evaluate the degree of AS.High-gradient aortic stenosis was defined mean gradient ≥ 40 mmHg, peak velocity ≥ 4.0 m/s, valve area ≤ 1 cm2 (or ≤ 0.6 cm²/m²; low-flow low-gradient aortic stenosis with reduced ejection fraction was defined mean gradient < 40 mmHg, valve area ≤ 1 cm2, LVEF < 50%, SVi ≤ 35 mL/m2; low-flow, low-gradient aortic stenosis with preserved ejection fraction was defined mean gradient < 40 mmHg, valve area ≤ 1 cm2, LVEF ≥ 50%, SVi ≤ 35 mL/m2.The patients were evaluated for the suitability of intervention by the heart team.The decision between SAVR and TAVI in patients who are at increased surgical risk (STS score or EuroSCORE II ≥ 4% or other risk factors not included in these scores, such as frailty, porcelain aorta, sequelae of chest radiotherapy) was made according to individual patient characteristics.
The exclusion criteria included aortic mechanic or biological prosthesis, bicuspid aorta, recent myocardial infarction within the last 3 months, left ventricular or aortic thrombus, cerebrovascular event history, thrombocytopenia (platelet count < 50,000/mm 3 ), baseline NSE elevation, severe mental disorder, drug/alcohol addiction, life expectancy < 1 year, short distance between coronary ostia and aortic valve annulus, size of aortic valve annulus out of range for TAVI and patients who underwent non-transfemoral TAVI.
Diabetes mellitus was present if the patient was taking anti-diabetic medication or HbA 1C level > 6.5%, or any glucose level > 200 mg/dl.Chronic kidney disease was defined as glomerular filtration rate < 60 ml/min.Peripheral artery disease was present if the patient had > 50% stenosis diagnosed with imaging modalities such as Doppler ultrasonography (USG) or computed tomography angiography (CTA) in any peripheral arteries.Chronic obstructive pulmonary disease (COPD) was defined according to the pulmonary function tests and classified as none, mild, moderate and severe.

Cardiac computed tomography evaluation
Before the procedure, all of the patients underwent cardiac computed tomography (CCT) with retrospective ECGgated acquisition to determine aortic valve anatomy, annular size and shape, extent and distribution of valve and vascular calcification, risk of coronary ostial obstruction, aortic root dimensions, optimal fluoroscopic projections for valve deployment, and feasibility of vascular access.Total cusp calcification volume was also recorded for each patient.Since intravascular attenuation and the attenuation of calcium in cardiac CTA are susceptible to changes in contrast delivery and tube voltage settings, we were not able to select a single cut-off value for the semi-automatic segmentation of calcium.To overcome this problem, pixel value mapping was applied per patient in the combined segmented 3D volumes to identify the main components (contrast material and calcium).A patient specific cut-off value was automatically selected, based on these main components and used to create binary masks.These masks, containing all pixels with a pixel value higher than the selected cutoff value (a pixel value higher than contrast material), were used to segment the calcium from each individual segment.and quantify paravalvular leaks or detect a significant pericardial effusion.The femoral artery entry site was closed surgically or by using a percutaneous vascular closure device (Proglide, Abbott Vascular, Santa Clara, CA, USA).Peripheral angiography was performed to evaluate vascular leak.Temporary pacemaker has been removed just after the procedure in most of the patients who did not develop 2nd or 3rd degree AV block during the procedure.Procedural success and any complications were defined according to the VARC-2 consensus.[17].

Determination of silent cerebral ischemia (SCI)
Neuron specific enolase (NSE) was used to detect SCI in all patients undergoing TAVI.Venous blood samples were obtained for NSE measurement at baseline and 12-24 h after the TAVI procedure.NSE was measured with NSE kits (Diametra, Foligno, Italy) using Enzyme-Linked Immunosorbent Assay (ELISA) analyser.0.12 µg/dl (12 ng/mL) was used as the cut-off for NSE positivity according to the instructions of manufacturer.A recent SCI was detected if post-procedural NSE levels were > 12 ng/mL.

Determination of silent cerebral ischemia with MRI
MRI protocol 1.5-T diffusion weighted (DW)-MRI (Aera MR, Germany) was performed on the patients 24 h after the TAVI procedure.All scans were analysed by an independent neurologist who was unaware of the procedural details.SCI was described to be appearing as hyperintense on DW-MRI and hypointense on apparent diffusion coefficient (ADC) (Fig. 3).The neurologist described the SCI lesions and evaluated its features.

Statistical methods
Continuous variables are presented as the mean ± SD, and categorical variables are presented as count and percentage.The distribution of continuous variables was assessed by the histogram test.Student's t-test or the Mann-Whitney U test were used to compare continuous variables in the two groups according to the distribution of variables.The chisquare test or Fisher's exact test were used to compare categorical variables.Spearman correlation coefficient was used for correlation analysis.Variables in multivariable regression analysis were choose according to univariable screening results, literature, and our focused variable.The results were represented as hazard ratio (HR) with 95% confidence intervals (CI).A two tailed P value < 0.05 was considered to be statistically significant.All analyses were performed using rms, ggplot, and Hmisc packages in R (version 4.01; The R Project for Statistical Computing, Vienna, Austria).
Calcium volume was calculated by multiplying the pixels by the pixel dimensions.

TAVI procedure
The TAVI procedure was performed by a single experienced first operator (UA) and an experienced second operator (MY and GE).The transfemoral approach is used in all of the included patients.One of the femoral arteries was cannulated for contrast agent injection and one of the femoral veins for the pacemaker.All TAVI patients require a temporary pacemaker, which is usually performed by insertion of a temporary pace electrode through the femoral vein.A pigtail catheter was placed in the aortic root, and a pacemaker lead was placed in the right ventricle.Then the contralateral femoral artery was cannulated surgically or percutaneously.Anticoagulation was provided with unfractionated heparin to maintain ACT > 300 s.The calcified valve was passed through with a straight tipped guidewire with the help of an AL-1 or AL-2 diagnostic catheter.Then the diagnostic catheter was improved into the left ventricle and the straighttipped wire in the left ventricular cavity was replaced with a stiff wire (Confida, Medtronic, Minneapolis, Minnesota, USA) with a flexible tip to minimize the risk of rupture with the aid of a pigtail catheter.The Evolut-R valve was released slowly under fluoroscopy using the tri-cusp views and cusp overlap technique at the aortic root with the help of a conveyor system and automatically expanded and placed in place.During valve implantation, heart rate was increased to a rate of 120-140/min to stabilize the valve.In the routine pre-BAV group, before valve implantation, the stenotic valve was dilated by balloon valvuloplasty (Fig. 2A).During the balloon valvuloplasty procedure, short-term ventricular pacing was performed at a rate of 180-200/min to minimize heart movement and prevent the balloon from slipping.In the direct TAVI group, no pre-dilation was performed, but the valve was implanted directly (Fig. 2B).In case the TAVI valve could not be improved into the LV or the AL-2 diagnostic catheter passage into the LV was difficult, the operator chose to perform pre-BAV in the direct TAVI group.In all of the cases, after valve was being implanted up to 90%, the implantation site was checked again whether to fully release the valve or not.If the operator did not find its implantation site proper enough, i.e. either too deep or too high, then the valve was retrieved and reimplanted.The success at first try was noted.If necessary for both groups in case of severe aortic regurgitation or insufficient expansion of the valve, post-dilation with a proper sized balloon was performed (Fig. 2C).After the procedure, paravalvular leakage was evaluated by aortography.If paravalvular leaks and/or pericardial effusion is suspected with fluoroscopy, transthoracic echocardiography was performed to evaluate 1 3 tomographic findings also did not differ between groups (Table 2).
TAVI procedure was successful in all of the study population.According to the VARC-2 classification, success rates were 77.1% in the routine pre-BAV group and 79.7% in the direct TAVI group (p = 0.71).Post-dilatation rates were higher in the direct TAVI group (Table 3).In 2 patients in the direct TAVI group, we had to use balloon pre-dilatation.The valve could not be improved into the LV in the first case, and in the other one, AL2 catheter improvement into the LV was impossible.TAVI procedure was successful in these patients but both of them had increased NSE levels after the procedure (38 ng/ml and 32 ng/ml) and new SCI

Results
Among 172 patients screened for eligibility, 33 were excluded due to the exclusion criteria (7 bio-prosthesis, 6 bicuspid aorta, 6 cerebrovascular event history, 2 thrombocytopenia, 6 baseline NSE elevation, 2 life expectancy < 1 year and 4 non-transfemoral TAVI) and 139 were included.First 70 patients underwent routine pre-BAV before prosthetic valve implantation and last 69 patients were intended to undergo direct TAVI.
Baseline clinical characteristics were similar between groups (Table 1).Baseline echocardiographic and computed  5).

Discussion
In this randomised prospective study, the main finding was the increased SCI rate demonstrated by new NSE elevations and diffusion MR imaging in patients undergoing routine pre-dilation before valve implantation when compared to the direct TAVI method.Besides presence of DM, calcification at arcus aorta, and higher cusp calcification volume increased the prevalence of SCI in patients undergoing TAVI.Another important finding was the increased risk of SCI in case of failure at the first try of self-expandable valve implantation and prosthetic valve retrieval and re-implantation.
In this study, we used both a bio-marker, NSE and diffusion MR imaging in eligible patients to show SCI development.New NSE elevations were significantly correlated with diffusion MR imaging results (r = 0.908,p < 0.001) in eligible patients.Due to this significant correlation, we used only new NSE elevations (studied in whole population) as the marker of SCI in our study.Besides, NSE was also studied as a good marker for SCI development in previous studies in several patient populations [18][19][20][21][22].
was confirmed with diffusion MR imaging.In the routine BAV group one patient had stroke and in the direct TAVI group, one patient died due to acute renal failure at the 6th day of the operation.No other mortality was seen in both groups in 30 days.Post-operative paravalvular leak rate was also similar when two groups were compared (Table 3).
The presence of AF and DM, total cusp calcification volume, calcification at arcus aorta, routine pre-BAV and failure at first try of the prosthetic valve implantation were significantly higher in SCI (+) group (Table 5).As a result, we used post-TAVI NSE positivity as a surrogate marker for SCI detection in whole population because in whole population, NSE could be studied.Other post-TAVI results of the patient population can be seen in Table 3.
Table 5 shows the correlation and multivariate analysis of the study parameters with SCI development.In the Fig. 3 In the right temporal lobe, a focal millimetric lesion consistent with acute ischemia is observed in the superior temporal gyrus appearing as hyperintense on diffusion-weighted imaging (DWI) and hypointense on apparent diffusion coefficient (ADC).
TAVI group in two patients.In one of these patients, the valve could not be improved into the LV and in the other one, AL2 catheter improvement was impossible, instead a 6 F JR4 catheter was used to get into the LV.These two patients who were included in the direct TAVI group had elevated NSE levels and SCI was also detected with diffusion MR imaging.As a result, despite this cross-over, the results were not expected to change significantly and were similar with the main results of the study.
The decrease of SCI with avoidance of pre-dilation might be explained by the fact that less manipulation with catheters decreases the embolization risk.Besides, balloon valvotomy might result in more separation of the calcium debris from the native valve.In the literature, no randomised study is found comparing SCI risk with vs. without pre-dilation, but some studies show that during pre-dilation, the risk of SCI could increase due to fragmentation of calcific debris present on a heavily calcified degenerative valve [33] as SCIs are common after many cardiac interventions including coronary angiography, percutaneous coronary interventions, pulmonary vein isolation and CABG operation [23][24][25].TAVI is the leading procedure among these with an incidence of > 70% in previous reports [11,[26][27][28][29][30][31][32].Herein, we have encountered with a rate of 70.5% in the whole population and 62% in the pre-dilation group.This decrease in SCI rates in our study population was thought to be due to the presence of a direct TAVI group with lower SCI rates.
Direct TAVI implantation without pre-dilation has become popular in the recent years.It has some advantages due to by-passing the risk of several complications which might be a result of balloon valvuloplasty including aortic regurgitation, annular rupture and hemodynamic instability due to rapid pacing.Two randomised clinical studies also demonstrated the safety and efficacy of direct TAVI method [5,6].However, balloon pre-dilation may be necessary in some cases.In this study, we used pre-dilation in the direct SCI rates were higher in case of failure at the first try of implantation and retrieval and reimplantation.This finding also supports the theory that additional manipulations during TAVI increase SCI rate.
Other factors were also found to be related with the development of SCI in patients undergoing TAVI.DM was an important but a non-surprising factor, because diabetic patients have a lower threshold for development of an ischemic cerebrovascular event [38].Calcification at arcus aorta was also related with new SCI development.As expected, passage of the guidewires, catheters and the bulky valve demonstrated by transcranial Doppler signals [34,35] but the same Doppler studies also showed that positioning of the new valve and fast pacing during deployment were associated with the highest embolic load.Besides, fast pacing during pre-dilation might have caused transient ischemia.Some controversies also exist in the literature so that avoidance of pre-dilation increased cerebral emboli risk in a study by Bijuklic et al[36].This might have been speculated to be due to difficulty while crossing the native valve and therefore additional manipulations which might have increased embolization risk [36,37].However, in this study, we have found for the first time in a randomised study that avoidance of pre-dilation decreases the likelihood of SCI development.This result may be due to the new generation Evolut-R valve use which has a better profile and easier passage through the calcified valve which decreases the additional manipulation need.Besides, in this study we have also found that affect SCI risk in these patients.New pacemaker rate was low in our study group when compared to the similar studies.This was thought to be due to high implantation with cusp overlap technique.There were several limitations of the current study.First of all, we could not get an MR imaging in the whole population because of some contraindications of MRI including presence of a pacemaker or any other prosthesis.However, NSE was significantly correlated with the MRI results and in all patients, NSE was measured to find out new SCIs.Besides, in this study, we did not use embolic protection devices during the TAVI procedure, however these devices have not been proven clinically effective till now.

Conclusions
Direct TAVI procedure without pre-dilation seems to be an effective method and avoidance of pre-dilation decreases the risk of SCI development in patients undergoing TAVI with a self-expandable valve.
from the atherosclerotic arcus aorta should have increased the likelihood of plaque embolization.Total calcium debris detected with cusp calcification volume was also an important risk factor for SCI development in this patient group.This has been also proved in a previous study by Bron et al. [32].
Similar to the literature, we have also found that direct TAVI is an effective method without increasing the complication rates.The post-dilation rate was also higher in the direct TAVI group when compared to the pre-dilation group similar to the literature.However, post-dilation did not

Fig. 1
Fig. 1 Randomisation chart of the patients

Table 1
Baseline clinical characteristics of the patients Numerical variables are presented as mean ± SD and categorical variables as percentages BAV: Balloon aortic valvuloplasty; TAVI: Transcatheter aortic valve implantation; DM: Diabetes mellitus; HPL: Hyperlipidemia; CABG: Coronary artery by-pass graft operation; PAD: Peripheral artery disease; LVEF: Left ventricular ejection fraction; STS: Society of Thoracic Surgeons; COPD: Chronic obstructive pulmonary disease; AICD: Automatic implantable cardioverter-defibrillator

Table 2
Numerical variables are presented as mean ± SD and categorical variables as percentages.AV: Aortic valve; AVA: Aortic valve area; AVAi: Indexed aortic valve area; PASP: Pulmonary arterial systolic pressure; LVOT: Left ventricular outflow tract

Table 3
Post-TAVI results of the study population

Table 4
Correlation between NSE levels and study parameters and multivariate analysis of the corresponding risk factors for SCI devel-