Does renal denervation require cardiovascular outcome-driven data?

Hypertension is a major driver of cardiovascular disease with a prevalence of 32-34% in adults worldwide. This poses a formidable unmet challenge for healthcare systems, highlighting the need for enhanced treatment strategies. Since 2017, eight major sham-controlled randomised controlled trials have examined the effectiveness and safety of renal denervation (RDN) as therapy for BP control. Although most trials demonstrated a reduction in systolic 24-hour/daytime ambulatory BP compared to control groups, open to discussion is whether major adverse cardiovascular events (MACE)-driven RDN trials are necessary or whether the proof of BP reduction as a surrogate for better cardiovascular outcomes is sufficient. We conducted an analysis of the statistical methods used in various trials to assess endpoint definitions and determine the necessity for MACE-driven outcome data. Such comprehensive analysis provides further evidence to confidently conclude that RDN significantly reduces blood pressure compared to sham controls. Importantly, this enables the interpolation of RDN trial endpoints with other studies that report on outcome data, such as pharmacological trials which demonstrate a significant reduction in MACE risk with a decrease in BP. Moreover, limitations associated with directly evaluating outcome data further support the use of BP as a surrogate endpoint. For example, conducting lengthier trials with larger numbers of participants to ensure robust statistical power presents a substantial challenge to evaluating outcome data. Thus, in light of the crucial need to tackle hypertension, there are notable advantages of considering BP as a surrogate for outcome data.

Peak Atrial Longitudinal Strain and Risk Stratification in Moderate and Severe Aortic Stenosis.

AIMS: We sought to investigate the association with outcome of left atrial strain in a large cohort of patients with at least moderate aortic stenosis (AS). METHODS AND RESULTS: we analyzed 467 patients (mean age 80.6 ± 8.2 years; 51% men) with at least moderate AS, and sinus rhythm. The primary study endpoint was the composite of all-cause mortality and hospitalizations for heart failure. After a median follow-up of 19.2 (IQR 12.5-24.4) months, 96 events occurred. Using the ROC curve analysis, the cut-off value of peak atrial longitudinal strain (PALS) more strongly associated with outcome was < 16% [AUC 0.70 (95% CI: 0.63-0.78), p<0.001]. The Kaplan Meier curves demonstrated a higher rate of events for patients with PALS<16% (log-rank p<0.001). On multivariable analysis, PALS [aHR 0.95 (95% CI 0.91 - 0.99), p=0.017] and age were the only variables independently associated with the combined endpoint. PALS provided incremental prognostic value over left ventricular (LV) global longitudinal strain, LV ejection fraction, and right ventricular function. Subgroup analysis revealed that impaired PALS was independently associated with outcome also in the subgroups of paucisymptomatic patients [aHR 0.98 (95% CI 0.97 - 0.98), p=0.048], moderate AS [aHR 0.92, (95% CI 0.86 - 0.98), p=0.016], and low-flow AS [aHR 0.90, (95% CI 0.83 - 0.98), p=0.020]. CONCLUSION: In our patients with at least moderate AS, PALS was independently associated with outcome. In asymptomatic patients, PALS could be a potential marker of subclinical damage, leading to better risk stratification, and, potentially, to earlier treatment.

Coronary microvascular dysfunction in patients undergoing transcatheter aortic valve implantation.

OBJECTIVES: This study aimed to evaluate the prognostic value of coronary microvascular dysfunction (CMD) at long term after transcatheter aortic valve implantation (TAVI) and to explore its relationship with extravalvular cardiac damage (EVCD). Moreover, we sought to test the correlation between angiography-derived index of microcirculatory resistance (IMRangio) and invasive IMR in patients with aortic stenosis (AS). METHODS: This was a retrospective analysis of the Verona Valvular Heart Disease Registry (Italy) including 250 patients (83 (80-86) years, 53% female) with severe AS who underwent TAVI between 2019 and 2021. IMRangio was calculated offline using a computational flow model applied to coronary angiography obtained during the TAVI workup. CMD was defined as IMRangio ≥30 units.The primary endpoint was the composite of cardiovascular death and rehospitalisation for heart failure (HF). Advanced EVCD was defined as pulmonary circulation impairment, severe tricuspid regurgitation or right ventricular dysfunction.The correlation between IMR and IMRangio was prospectively assessed in 31 patients undergoing TAVI. RESULTS: The primary endpoint occurred in 28 (11.2%) patients at a median follow-up of 22 (IQR 12-30) months. Patients with CMD met the primary endpoint more frequently than those without CMD (22.9% vs 2.8%, p<0.0001). Patients with CMD were more frequently characterised by advanced EVCD (33 (31.4%) vs 27 (18.6%), p=0.024). CMD was an independent predictor of adverse outcomes (adjusted HR 6.672 (2.251 to 19.778), p=0.001) and provided incremental prognostic value compared with conventional clinical and imaging variables. IMRangio demonstrated fair correlation with IMR. CONCLUSIONS: CMD is an independent predictor of cardiovascular mortality and HF after TAVI.

Integrated Assessment of Computational Coronary Physiology From a Single Angiographic View in Patients Undergoing TAVI.

BACKGROUND: Angiography-derived computational physiology is an appealing alternative to pressure-wire coronary physiology assessment. However, little is known about its reliability in the setting of severe aortic stenosis. This study sought to provide an integrated assessment of epicardial and microvascular coronary circulation by means of single-view angiography-derived physiology in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI). METHODS: Pre-TAVI angiographic projections of 198 stenotic coronary arteries (123 patients) were analyzed by means of Murray's law-based quantitative flow ratio and angiography microvascular resistance. Wire-based reference measurements were available for comparison: fractional flow reserve (FFR) in all cases, instantaneous wave-free ratio in 148, and index of microvascular resistance in 42 arteries. RESULTS: No difference in terms of the number of ischemia-causing stenoses was detected between FFR ≤0.80 and Murray's law-based quantitative flow ratio ≤0.80 (19.7% versus 19.2%; P=0.899), while this was significantly higher when instantaneous wave-free ratio ≤0.89 (44.6%; P=0.001) was used. The accuracy of Murray's law-based quantitative flow ratio ≤0.80 in predicting pre-TAVI FFR ≤0.80 was significantly higher than the accuracy of instantaneous wave-free ratio ≤0.89 (93.4% versus 77.0%; P=0.001), driven by a higher positive predictive value (86.9% versus 50%). Similar findings were observed when considering post-TAVI FFR ≤0.80 as reference. In 82 cases with post-TAVI angiographic projections, Murray's law-based quantitative flow ratio values remained stable, with a low rate of reclassification of stenosis significance (9.9%), similar to FFR and instantaneous wave-free ratio. Angiography microvascular resistance demonstrated a significant correlation (Rho=0.458; P=0.002) with index of microvascular resistance, showing an area under the curve of 0.887 (95% CI, 0.752-0.964) in predicting index of microvascular resistance ≥25. CONCLUSIONS: Angiography-derived physiology provides a valid, reliable, and systematic assessment of the coronary circulation in a complex scenario, such as severe aortic stenosis.

Comparison of different percutaneous revascularisation timing strategies in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: The optimal timing to perform percutaneous coronary interventions (PCI) in transcatheter aortic valve implantation (TAVI) patients remains unknown. AIMS: We sought to compare different PCI timing strategies in TAVI patients. METHODS: The REVASC-TAVI registry is an international registry including patients undergoing TAVI with significant, stable coronary artery disease (CAD) at preprocedural workup. In this analysis, patients scheduled to undergo PCI before, after or concomitantly with TAVI were included. The main endpoints were all-cause death and a composite of all-cause death, stroke, myocardial infarction (MI) or rehospitalisation for congestive heart failure (CHF) at 2 years. Outcomes were adjusted using the inverse probability treatment weighting (IPTW) method. RESULTS: A total of 1,603 patients were included. PCI was performed before, after or concomitantly with TAVI in 65.6% (n=1,052), 9.8% (n=157) or 24.6% (n=394), respectively. At 2 years, all-cause death was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (6.8% vs 20.1% vs 20.6%; p<0.001). Likewise, the composite endpoint was significantly lower in patients undergoing PCI after TAVI as compared with PCI before or concomitantly with TAVI (17.4% vs 30.4% vs 30.0%; p=0.003). Results were confirmed at landmark analyses considering events from 0 to 30 days and from 31 to 720 days. CONCLUSIONS: In patients with severe aortic stenosis and stable coronary artery disease scheduled for TAVI, performance of PCI after TAVI seems to be associated with improved 2-year clinical outcomes compared with other revascularisation timing strategies. These results need to be confirmed in randomised clinical trials.

Management of Myocardial Revascularization in Patients With Stable Coronary Artery Disease Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND: The best management of stable coronary artery disease (CAD) in patients undergoing transcatheter aortic valve implantation (TAVI) is still unclear due to the marked inconsistency of the available evidence. METHODS: The REVASC-TAVI registry (Management of Myocardial Revascularization in Patients Undergoing Transcatheter Aortic Valve Implantation With Coronary Artery Disease) collected data from 30 centers worldwide on patients undergoing TAVI who had significant, stable CAD at preprocedural work-up. For the purposes of this analysis, patients with either complete or incomplete myocardial revascularization were compared in a propensity score matched analysis, to take into account of baseline confounders. The primary and co-primary outcomes were all-cause death and the composite of all-cause death, stroke, myocardial infarction, and rehospitalization for heart failure, respectively, at 2 years. RESULTS: Among 2407 patients enrolled, 675 pairs of patients achieving complete or incomplete myocardial revascularization were matched. The primary (21.6% versus 18.2%, hazard ratio' 0.88 [95% CI, 0.66-1.18]; P=0.38) and co-primary composite (29.0% versus 27.1%, hazard ratio' 0.97 [95% CI, 0.76-1.24]; P=0.83) outcome did not differ between patients achieving complete or incomplete myocardial revascularization, respectively. These results were consistent across different prespecified subgroups of patients (< or >75 years of age, Society of Thoracic Surgeons score > or <4%, angina at baseline, diabetes, left ventricular ejection fraction > or <40%, New York Heart Association class I/II or III/IV, renal failure, proximal CAD, multivessel CAD, and left main/proximal anterior descending artery CAD; all P values for interaction >0.10). CONCLUSIONS: The present analysis of the REVASC-TAVI registry showed that, among TAVI patients with significant stable CAD found during the TAVI work-up, completeness of myocardial revascularization achieved either staged or concomitantly with TAVI was similar to a strategy of incomplete revascularization in reducing the risk of all cause death, as well as the risk of death, stroke, myocardial infarction, and rehospitalization for heart failure at 2 years, regardless of the clinical and anatomical situations.

Optimal timing for percutaneous coronary intervention in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: The best timing to perform percutaneous coronary interventions (PCI) in patients undergoing TAVI is unknown. Most PCI are performed before TAVI, because of concerns about potential ischemic complications during valve implantation. In this study we aimed to compare short-and long-term outcomes of patients undergoing PCI before or after TAVI. METHODS: Patients undergoing TAVI and PCI from 2010 to 2021 were analyzed. PCI was defined as high-risk when involving unprotected left main, proximal left anterior descending, proximal dominant right coronary artery or 3-vessel disease. The primary endpoint was the cumulative incidence of any TAVI procedural complication and in-hospital adverse events (VARC-3 criteria). RESULTS: Out of 1162 patients, 144 underwent PCI, 68% after TAVI, 78.4% of which were at high-risk. The primary endpoint occurred in 28.4% of patients in PCI pre-TAVI group vs 21.4% in PCI post-TAVI group (p = 0.403) and in 34.4% vs 17.3% of patients respectively among high-risk patients (p = 0.075). A higher rate of stroke was observed in the PCI pre-TAVI group regardless of the PCI complexity (6.5% vs 0.0%, p = 0.031; 9.3% vs 0.0% p = 0.025 in the high-risk group). At 24 months, MACCE-free survival was lower in patients who underwent PCI before TAVI (84.4% vs 97.9%, adjusted HR 10.16, 95% CI 1.19-86.57, p = 0.019; and 84.4% vs 97.3%, adjusted HR 7.34 95% CI 0.78-62.28 p = 0.082 in the high-risk group). CONCLUSIONS: PCI performed after TAVI does not expose patients to higher risks of peri-procedural hazards and provides a trend towards favourable clinical outcome at mid-to-long term.

Incomplete Functional Revascularization Is Associated With Adverse Clinical Outcomes After Transcatheter Aortic Valve Implantation.

BACKGROUND AND PURPOSE: Whether incomplete functional revascularization has an impact on the clinical outcome of patients treated with transcatheter aortic valve implantation (TAVI) is still unknown. We aim to assess the prognostic value of residual functional SYNTAX score (rFSS) in a cohort of patients undergoing TAVI. METHODS AND RESULTS: One-hundred-twenty-four patients (229 lesions) with severe aortic stenosis and coronary artery disease (CAD) underwent fractional flow reserve (FFR)-guided revascularization. The primary endpoint of the study was the composite of cardiac death, myocardial infarction, and revascularization at the last available follow-up after TAVI. Median SYNTAX score (SS) and Functional SYNTAX score (FSS) at baseline were 7 (range 5-12) and 0 (range 0-7) respectively. After revascularization or deferral according to FFR, residual SS (rSS) and rFSS were 5 (range 0-8) and 0 (range 0-0) respectively. Angiographic incomplete revascularization (rSS > 0) was not associated with the primary endpoint (HR 1.2; 95% CI 0.4-3.9; p = 0.69), whereas functional incomplete revascularization (rFSS>0) was associated with worse event-free survival at follow up after adjusting for clinical confounders (HR 3.7; 95% CI 1.0-13.7; p = 0.04). CONCLUSION: Incomplete functional revascularization is associated with adverse clinical outcomes after TAVI. Residual functional SYNTAX score may be regarded as a treatment goal for patients with CAD undergoing TAVI. Further studies are warranted to confirm our hypothesis.

Volume of contrast to creatinine clearance ratio predicts early mortality and AKI after TAVI.

The volume of contrast to creatinine clearance ratio (CV/CrCl) is a useful indicator of the risk of acute kidney injury (AKI) in patients undergoing percutaneous interventional procedures. Association between CV/CrCl and adverse outcome after transcatheter aortic valve implantation (TAVI) was suggested but it is not well established. A large retrospective multicenter cohort of 1381 patients treated with TAVI was analyzed to assess the association between CV/CrCl and the risk of AKI and mortality at 90 days and 1 year after TAVI. Patients receiving renal replacement therapy at the time of TAVI were excluded. CV/CrCl ≥ 2.2 was associated with the risk of AKI and 90 days mortality after TAVI after adjustment for age, sex, diabetes, baseline left ventricular function, baseline chronic kidney disease (CKD), previous myocardial infarction and peripheral vascular disease (hazard ratio [HR]: 1.16, 95% confidence interval [CI]: 1.09-1.22, p < 0.0001). Importantly, CV/CrCl was associated with the adverse outcome independently from the presence of baseline CKD (p for interaction = 0.22). CV/CrCl was independently associated with the individual components of the composite primary outcome including AKI (odds ratio: 1.18, 95% CI: 1.08-1.28, p < 0.0001) and 90 days mortality (HR: 1.90, 95% CI: 1.01-3.60, p = 0.047) after TAVI. AKI (HR: 1.94, 95% CI: 1.21-3.11, p = 0.006) but not CV/CrCl was associated with the risk of 1-year mortality after TAVI. CV/CrCl is associated with excess renal damage and early mortality after TAVI. Procedural strategies to minimize the CV/CrCl during TAVI may improve early clinical outcomes in patients undergoing TAVI.

Impact of physiologically diffuse versus focal pattern of coronary disease on quantitative flow reserve diagnostic accuracy.

BACKGROUND: Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) disagree in about 20% of intermediate coronary lesions. As the physiological pattern of coronary artery disease has a significant influence on FFR-iFR discordance, we sought to assess it may impact on the diagnostic accuracy of quantitative flow reserve (QFR). METHODS: One hundred and ninety-four patients with 224 intermediate coronary lesions were investigated with iFR, FFR, and QFR. The physiological pattern of disease was assessed with iFR Scout pullback and QFR virtual pullback in all the cases. RESULTS: A predominantly physiologically focal pattern was observed in 81 (36.2%) lesions, whereas a predominantly physiologically diffuse was observed in 143 (63.8%) cases. QFR demonstrated a significant correlation (r = 0.581, p < 0.001) and a substantial agreement with iFR, both in diffuse (AUC = 0.798) and in focal (AUC = 0.812) pattern of disease. Discordance between QFR and iFR was observed in 51 (22.8%) lesions, consisting of iFR+/QFR- (64.7%) and iFR-/QFR+ (35.3%). Notably, the physiological pattern of disease was the only variable significantly associated with iFR/QFR discordance. QFR virtual pullback demonstrated an excellent agreement (83.9%) with iFR Scout pullback in classifying the physiological pattern of disease. CONCLUSIONS: QFR has a good diagnostic accuracy in assessing myocardial ischemia independently of the pattern of coronary disease. However, the physiological pattern of disease has an influence on the QFR/iFR discordance, which occurs in ~20% of the cases. The QFR virtual pullback correctly defined the physiological pattern of disease in the majority of the cases using the iFR pullback as reference.

Contrast-Induced Nephropathy in Patients Undergoing Staged Versus Concomitant Transcatheter Aortic Valve Implantation and Coronary Procedures.

Background The impact of staged versus concomitant coronary procedures on renal function in patients with aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) remains unclear. Methods and Results Three-hundred thirty-nine patients undergoing coronary procedures and TAVI as a staged strategy (160, 47.2%) or concomitant strategy (179, 52.8%) were retrospectively analyzed. Contrast-induced acute kidney injury (CI-AKI) occurred in 49 patients in the staged strategy group (30.6%) and in 18 patients (10.1%) in the concomitant strategy group (P<0.001). Among the staged strategy group, 25 (15.6%) patients developed CI-AKI after coronary angiography or percutaneous coronary intervention, 17 (10.6%) after TAVI, and 7 (4.3%) after both the procedures. Staged strategy was associated with a higher risk of CI-AKI (odds ratio, 3.948; P<0.001) after adjustment for multiple confounders and regardless of the baseline renal function (P for interaction=0.4) when compared with the concomitant strategy. At a median follow-up of 24.0 months (3.0-35.3), CI-AKI was not associated with sustained renal injury (P=0.794), irrespective of the adopted strategy. The concomitant strategy did not impact the overall early safety at 30 days follow-up after TAVI compared to the staged strategy (P=0.609). Conclusions Performing coronary procedures with a staged strategy before TAVI was associated with a higher risk of CI-AKI compared with a concomitant strategy. Moreover, a concomitant strategy did not increase the risk of procedure-related complications.

Impact of Left Ventricular Outflow Tract Calcification on Pacemaker Implantation After Transcatheter Aortic Valve Implantation With Second-Generation Devices.

OBJECTIVE: To evaluate the impact of left ventricular outflow tract calcification (LVOT-CA) localization and extension on permanent pacemaker implantation (PPI) rates after transcatheter aortic valve implantation (TAVI) with second-generation devices. METHODS: This single-center retrospective study included all consecutive patients who underwent transfemoral TAVI with second-generation devices at San Raffaele Hospital in Milan, Italy from January 2014 to June 2017. The localization and extension of LVOT-CA were evaluated using computed tomography imaging; LVOT regions were categorized according to the overlying coronary cusps. RESULTS: The study population consisted of 377 patients, of which LVOT-CA was present in 133 patients (35.3%). Patients with LVOT-CA had significantly a higher rate of post-TAVI PPI (32.0% vs 19.2% in patients with no LVOT-CA; P<.01). Multivariable analysis demonstrated LVOT-CA in the non-coronary cusp, as well as preprocedural right bundle-branch block, age, body mass index, and mechanically expanded prosthesis implantation, to be strong independent predictors of PPI. CONCLUSIONS: LVOT-CA in the non-coronary cusp is a strong independent predictor of PPI after TAVI with second-generation devices. Further studies are needed to confirm these data in a larger, multicenter population.

Short-and-Long-Term Outcomes after Coronary Rotational Atherectomy in Patients Treated with Trans-Catheter Aortic Valve Implantation.

BACKGROUND: Coronary artery disease (CAD) is a common finding among patients undergoing trans-catheter aortic valve implantation (TAVI), who often present severely calcified coronary lesions. Evidence is scarce about the use of rotational atherectomy (RA) in this setting, in particular regarding long-term outcome. METHODS: RA was performed on severely calcified coronary lesions concomitant with TAVI in a consecutive series of patients treated between 2010 and 2020. Immediate and long-term clinical outcomes are reported. RESULTS: A concomitant CAD (coronary stenosis visually > 50%) was observed in 402/845 (47.6%) consecutive patients undergoing TAVI at the University Hospital of Verona. Angioplasty was performed in 104 patients (12.3%). Among these, 19 patients (18.3%, 20 coronary arteries), were treated with RA after TAVI: 10 after implantation of a balloon-expandable trans-catheter valve and 9 after a self-expandable valve. All procedures were successful. Hypotension occurred in 3 patients (15.8%), with rapid recovery after the procedure; CI-AKI (contrast-induced acute kidney injury) in 3 patients (15.8%), of which two recovered within discharge. At a median follow-up of 21.5 months (Q1-3: 6-36) event free survival was 83.3%. Only one patient suffered a target vessel failure >2 years after RA. Neither stroke nor peri-procedural infarctions were detected. CONCLUSIONS: RA concomitant with TAVI was feasible and safe in patients treated with implantation of either self-expandable, or balloon-expandable trans-catheter aortic valves. Long-term clinical events related to the coronary procedure were extremely infrequent and the survival rate at median follow-up of 21.5 months was 83.3%.

Anatomic and procedural associations of transcatheter heart valve displacement following Evolut R implantation.

OBJECTIVES: This study aimed to predict the displacement of self-expanding transcatheter heart valves (THV) during final deployment. BACKGROUND: Accurate device positioning during transcatheter aortic valve implantation (TAVI) is crucial for optimal results. METHODS: At our institution, 103 patients who underwent transfemoral TAVI with Evolut R were retrospectively identified. Multiple linear regression models were created, and a predictor equation was built to quantify the factors that may affect THV behavior. RESULTS: Multiple linear regression analysis for THV displacement on the left coronary cusp (LCC) identified the angle between the THV and the ascending aorta (ATA), predilation, and less operator experience as independent predictors of upward displacement, whereas estimated glomerular filtration rate (eGFR) was inversely related with THV behavior (95% confidence interval: 0.219 to 0.340, 0.447 to 2.092, 0.165 to 1.757, and -0.053 to -0.011, respectively). Predictors of THV displacement on the noncoronary cusp side could not be identified using this model. CONCLUSIONS: The ATA at the point of recapture, predilation, and less operator experience were independent predictors of upward displacement of THV on the LCC side. eGFR was an independent predictor of THV downward displacement on the LCC side. Of them, the ATA was the strongest predictor. Physicians may need to adjust this angle adequately before deployment to achieve the appropriate position.

Percutaneous Direct Annuloplasty With Edge-to-Edge Technique for Mitral Regurgitation: Replicating a Complete Surgical Mitral Repair in a One-Step Procedure.

Surgical treatment of functional mitral regurgitation (MR) is usually based on the correction of both annular dilation and leaflet disease to minimize the risk of recurrence of MR at follow-up. This combined approach may also represent an interesting strategy during transcatheter mitral valve repair systems. We report a successful case of combined Cardioband (Edwards Lifesciences, Irvine, California) and MitraClip (Abbott, Santa Clara, California) implantation for the treatment of functional MR, with good acute and medium-term clinical and echocardiographic outcomes.

Predilatation Prior to Transcatheter Aortic Valve Implantation: Is it Still a Prerequisite?

Predilatation has been historically considered a mandatory step before transcatheter aortic valve implantation (TAVI) since it facilitates valve crossing and prosthesis delivery, ensures optimal valve expansion and improves hemodynamic stability during valve deployment. However, as a result of procedural evolution over time, direct TAVI (without pre-implantation balloon aortic valvuloplasty) has emerged as an interesting option to simplify the procedure and to avoid potential valvuloplasty-related complications. Several real-world retrospective studies and one small randomised study have shown that direct TAVI (with both self-expanding and balloon-expandable prostheses) is feasible, safe and associated with outcomes similar to standard TAVI with pre-implantation balloon aortic valvuloplasty. In the absence of high-quality, robust evidence, the current review aims to discuss the advantages and disadvantages of omitting predilatation prior to TAVI.