
==== Front
JACC Adv
JACC Adv
JACC: Advances
2772-963X
Elsevier

S2772-963X(24)00473-3
10.1016/j.jacadv.2024.101242
101242
Original Research
Von Willebrand Factor Activity Association With Outcomes After Transcatheter Edge-to-Edge Mitral Valve Repair
Hadjadj Sandra MSc
Pibarot Philippe DVM, PhD
Gravel Caroline RN
Clavel Marie-Annick DVM, PhD
Marsit Ons PhD
Rouabhia Dounia MD
Labbé Benoît M. MD
O’Connor Kim MD
Bernier Mathieu MD
Salaun Erwan MD, PhD
Farjat Julio MD, MSc
Nuche Berenguer Jorge MD
Rodés-Cabau Josep MD
Paradis Jean-Michel MD
Beaudoin Jonathan MD jonathan.beaudoin@criucpq.ulaval.ca
∗
Quebec Heart and Lung Institute - Laval University, Quebec, Quebec, Canada
∗ Address for correspondence: Dr Jonathan Beaudoin, Institut Universitaire de Cardiologie et de Pneumologie de Québec – Université Laval, 2725 Chemin Ste-Foy, Québec G1V 4G5, Canada. jonathan.beaudoin@criucpq.ulaval.ca
10 9 2024
10 2024
10 9 2024
3 10 10124227 11 2023
11 7 2024
26 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

Residual mitral regurgitation (MR) is associated with worse outcomes after transcatheter edge-to-edge mitral valve repair (TEER). Shear stress induced by MR leads to altered von Willebrand factor activity (vWF:Act) and increased closure time with adenosine diphosphate (CT-ADP).

Objectives

The purpose of this study was to investigate the use of CT-ADP to monitor MR during TEER and the association between the vWF, residual MR, and clinical events post-TEER.

Methods

Sixty-five patients undergoing TEER were enrolled. CT-ADP was measured at baseline, after each clip deployment, 1 hour and 24 hours post-TEER. CT-ADP values were related to vWF:Act/vWF antigen (vWF:Ag) ratio at the same time points, and MR severity was assessed by echocardiography at 1 month. Combined events of all-cause mortality and heart failure hospitalizations were evaluated at 1 year.

Results

At 1 month, 32 (49%) patients had residual MR > mild (of those, 14% had MR > moderate). There was no significant change in CT-ADP values during the procedure. However, CT-ADP significantly decreased 1-hour post-TEER (P < 0.001). Patients with corrected MR demonstrated an increase in vWF:Act/vWF:Ag ratio 1-hour post-TEER. Elevated baseline vWF:Act/vWF:Ag ratio and the periprocedural percentage changes of the vWF:Act/vWF:Ag ratio (1 hour post-TEER – baseline values) were associated with the combined clinical outcome.

Conclusions

CT-ADP evolution in time was not quick enough to provide real-time monitoring of MR severity during TEER. However, vWF:Act/vWF:Ag ratio at baseline and its variations following the procedure were associated with clinical outcomes. Those findings will need external validation.

Central Illustration

Key words

CT-ADP
MitraClip
transcatheter mitral valve repair
von Willebrand diseases
von Willebrand factor
Abbreviations and Acronyms

CT-ADP closure time with adenosine diphosphate

HF heart failure

HMW high molecular weight

MR mitral regurgitation

TEER Transcatheter Edge-to-Edge Mitral Valve Repair

vWF:Act von Willebrand factor activity

vWF:Ag von Willebrand factor antigen
==== Body
pmcPersistent mitral regurgitation (MR) after transcatheter edge-to-edge mitral valve repair (TEER) is associated with increased rates of heart failure (HF) hospitalizations and mortality.1, 2, 3, 4, 5 Procedural decisions regarding adding multiple clips are led by echocardiographic and hemodynamic evaluation of residual MR and mitral gradient. However, MR assessment during TEER can be difficult, with potential multiple/eccentric jets and variable hemodynamic conditions under general anesthesia.6

High shear stress induced by MR leads to excessive cleavage of von Willebrand factor (vWF) multimers,7, 8, 9 resulting in a qualitative change in vWF, decreasing its activity (vWF:Act) without affecting the levels of vWF antigens (vWF:Ag). The ratio of vWF:Act/vWF:Ag has been used to document changes in turbulent flow associated with valvular regurgitation.8 However, comorbidities such as hypertension or atherosclerosis, which are common in patients considered for a TEER, can be confounders by affecting the clearance of vWF.10, 11, 12 Elevated plasma levels of vWF in patients with MR and comorbidities were previously associated with cardiovascular events.11,13, 14, 15

Closure time with adenosine diphosphate (CT-ADP) is a point-of-care measure of hemostasis strongly influenced by vWF:Act. CT-ADP can be assessed easily and serially during TEER and is known to normalize swiftly after the correction of turbulent flow. Its use has been described to screen for paravalvular leak during transcatheter aortic valve replacement,16 and could also represent a potential way to assess residual MR during TEER.8,17,18 Serial intraprocedural data of CT-ADP during TEER are, however, lacking.

The aims of the present study were to explore whether acute changes of CT-ADP and vWF:Act/vWF:Ag ratio (representing correction of turbulent flow) can be associated with residual MR and clinical events at 1 year postintervention. We also sought to investigate the association between baseline vWF levels (influenced by MR and comorbid conditions) and prognosis after TEER.

Material and methods

Study design

Consecutive patients with symptomatic MR who underwent TEER using MitraClip (Abbott) or Pascal device (Edwards Lifesciences) from December 2018 to May 2022 at the Quebec Heart and Lung Institute were prospectively included in the study (Figure 1). TEER procedures were performed per clinical protocol19,20 under anticoagulation with intravenous unfractionated heparin. Antithrombotic therapy after TEER was left at the physician’s discretion.Figure 1 Population and Exclusions

MR = mitral regurgitation.

Clinical and imaging follow-up

Transthoracic and transeosophageal echocardiography were performed using commercially available equipment VIVID E95 (GE Healthcare) and EPIQ7 (Philips Healthcare). Transthoracic and transeosophageal echocardiography were performed at baseline and 1-month post-TEER. MR severity was assessed according to current guidelines using a multiparametric approach.21,22 Residual MR was defined as MR grade > mild at 1 month. All echocardiography images were reviewed by a single level 3 reader (unaware of the biomarkers results or clinical events) for MR grade. In case of discrepancy between this assessment and the clinically reported MR grade, a third reader was involved and final MR grade was determined by consensus. All patients had a clinical visit or a follow-up call 12 months after TEER. The endpoints were defined according to the Mitral Valve Academic Research Consortium criteria.23 The primary objective was to explore the changes in CT-ADP and vWF levels, reflecting the evolution of turbulent flow during and after the procedure. We also looked at the combined event of all-cause mortality or HF hospitalizations and its association with biomarker values. This study was approved by the local institutional review board.

Laboratory analysis

Samples for measurements of von Willebrand factor activity (vWF:Act) and von Willebrand factor antigen (vFW:Ag) were collected at baseline (during the admission), 1 hour, and 24 hours (before discharge) after the procedure and were available in 60 patients. VWF:Act was analyzed using the INNOVANCE VWF Ac System (Siemens Healthineers), and vWF:Ag was measured by immunoturbidimetry (CA-5100, Sysmex). Rapid platelet function tests (CT-ADP) were performed at baseline (under anesthesia, before the femoral vein puncture), 8 minutes after the deployment of each clip, 1 hour and 24 hours after the procedure. Periprocedural serial measurements were available for 52 patients. CT-ADP tests were performed using the Platelet Function Analyzer 100 (PFA-100, Siemens Healthineers). The device aspirates blood from a sample into a membrane coated with collagen and adenosine diphosphate (ADP); platelet aggregation occludes an orifice in the membrane mimicking a vascular breach; and CT-ADP is the time to occlusion.

Statistical analysis

Categorical variables are presented as absolute or relative frequencies. Continuous variables are expressed as mean ± SD or as median (IQR) according to the variable distribution. The procedural evolution of vWF:Act/vWF:Ag ratio and CT-ADP are expressed as percentage change vs baseline. Biomarker levels were compared between patients who experienced or not a clinical event (mortality or HF hospitalization) using the Wilcoxon rank-sum test. The evolution of CT-ADP and vWF levels after TEER was analyzed with a linear mixed model with repeated measures. One fixed factor (time effect) with three levels (baseline, first, and last clip) was defined. A random intercept (subject effect) was added to the model. A second fixed factor (residual MR effect) was added to compare patients with residual vs corrected MR with an interaction term between the two fixed factors. The dependence between repeated measurements was modeled using an unstructured covariance matrix of correlation as some observations were missing. Posteriori comparisons were performed using the Tukey’s method. The normality assumption was verified with the Shapiro-Wilk test using residuals from the statistical model and transformed by the Cholesky's metric. The graphical representation of marginal linear predictor with studentized residuals suggested the homogeneity of variances. Some of the variables were log-transformed to fulfill these assumptions. Logistic regression analyses were performed to identify potential parameters that could be associated with residual MR24 and adjusted for age, sex, Society of Thoracic Surgeons score, and blood type separately as the number of patients was limited. Continuous variables were checked for the assumption of linearity in the logit using graphical representations. Cox proportional hazard regression analyses were performed to model event-free (all-cause mortality or HF hospitalization) follow-up. Variables from univariate analyses with a probability value <0.20 as well as those with biological plausibility were tested in multivariable analyses. Baseline vWF:Act/VWF:Ag and ΔvWF:Act/VWF:Ag% were adjusted for age, female sex, STS score, O blood type, tricuspid regurgitation (TR) > mild, and residual MR > mild in separate models as the number of events was small. The martingale residuals were used to examine the functional form of continuous variables (no transformation was necessary). Artificial time-dependent covariates (X[t] = log[t]·baseline vWF:Act/VWF:Ag and X[t] = log[t]·ΔvWF:Act/VWF:Ag%) were added to the univariate models to test the proportionality assumption. The proportional hazards assumption was not rejected as local test linked to the time-dependent covariates was not significant. Receiver operating characteristic analysis was performed for significant variables, with optimal threshold values determined by the Youden Index. Kaplan-Meier survival curves and their associated log-rank tests were used to compare all-cause mortality or HF hospitalizations in patients who had vWF:Act/vWF:Ag ratio >1.015 and patients not improving vWF activity after the procedure (ΔvWF:Act/VWF:Ag <5.5%). The statistical analysis was not planned for multiplicity of tests for secondary outcomes. All analyses were performed using GraphPad version 9.4.1 (GraphPad Software) and SAS version 9.4 (SAS Institute Inc).

Results

A total of 65 patients (37% women; age 76 ± 9 years) were included in the study. Baseline and procedural characteristics are listed in Table 1, and echocardiographic parameters are shown in Table 2. MR etiology was functional in 25 (39%) patients, organic in 34 (53%) patients, and mixed in 6 (9%) patients. After 1 month of follow-up, 32 (49%) patients had residual MR > mild; of those, 9 (14%) patients had MR > moderate. After a 1-year follow-up, clinical events (mortality or HF hospitalizations) occurred in 14 (22%) patients. Patients who experienced a clinical event had a higher STS score for mitral valve replacement (7.3 ± 3.2 vs 4.9 ± 3.5, P = 0.02) and lower 6-minute walking test results at baseline (224 ± 112 m vs 303 ± 126 m, P = 0.043). There was no difference in the prevalence of patients with an O blood type between groups. Patients with an O blood type demonstrated lower levels of vWF:Ag at baseline (1.64 [1.16-1.98] vs 2.08 [1.72-2.47] IU/ml; P = 0.002), without difference in vWF:Act/vWF:Ag ratio (0.99 [0.90-1.12] vs 0.95 [0.87-1.01]; P = 0.178) (Supplemental Table 1). There was significantly more TR at follow-up in patients with events (>mild: 79% vs 45%, P = 0.036). Otherwise, there was no statistical difference in terms of comorbidities or echocardiographic parameters between the two groups. Patients treated with antiplatelet therapies had no significant difference for CT-ADP and vWF levels at baseline (Supplemental Table 2).Table 1 Baseline and Procedural Characteristics of the Population (N = 65)

Clinical data		
 Age, y	76 ± 9	
 Female	24 (37)	
 Weight, kg	79 ± 25	
 Body surface area, m2	1.9 ± 0.3	
Comorbidities		
 Hypertension	50 (77)	
 Dyslipidemia	42 (65)	
 COPD	13 (20)	
 History of AF	33 (51)	
 CAD	34 (52)	
 Renal failurea	36 (55)	
Surgical risk		
 STS score MVR	5.5 ± 3.4	
Frailty		
 6 minutes walking test, m	284 ± 126	
 NYHA functional class ≥ III	50 (77)	
Laboratory data		
 NT-proBNP, pg/mL	2037 (1,001-3,699)	
 eGFR, mL/min/1.73 m2	57 (41-69)	
 O blood type	28 (43)	
Antithrombotic treatment		
 Antiplatelet therapy	23 (35)	
 Anticoagulation therapy	37 (57)	
Procedural characteristics		
 Procedural timing, min	115 ± 56	
 Number of clip(s)	2 ± 1	
Values are as mean ± SD, median (25th-75th percentiles), or n (%).

AF = atrial fibrillation; CAD = coronary artery disease; COPD = chronic obstructive pulmonary disease; eGFR = estimated glomerular filtration rate; NT-proBNP = natriuretic peptide; NYHA = New York Heart Association; MVR = mitral valve replacement; STS = Society of Thoracic Surgeons risk score.

a Renal failure if eGFR <60 ml/min/1.73 m2.

Table 2 Echocardiographic Parameters at Baseline and 1-Month Post-TEER (N = 65)

Baseline		
 LVEF, %	46 ± 13	
 LVEDD, cm	5.4 ± 0.9	
 LAVi, ml/m2	53 ± 21	
 PAPs, mm Hg	46 ± 17	
 MR etiology		
 Functional	25 (39)	
 Organic	34 (52)	
 Mixed	6 (9)	
 AR > mild	10 (15)	
 TR > mild	32 (49)	
 AS ≥ milda	6 (9)	
Follow-up		
 LVEF, %	45 ± 11	
 LVEDD, cm	5.4 ± 0.9	
 LAVi, ml/m2	55 ± 21	
 PAPs, mm Hg	43 ± 15	
 Residual MR		
 Trace/mild	33 (51)	
 Mild to moderate	18 (28)	
 Moderate	5 (8)	
 >Moderate	9 (14)	
 TR > mild	34 (52)	
 TMG, mm Hg	4.7 ± 3.1	
 TMG >5 mm Hg	16 (25)	
Values are mean ± SD or n (%).

AR = aortic regurgitation; AS = aortic stenosis; LAVi = indexed left atrial volume; LVEDD = left ventricle end-diastolic diameter; LVEF = left ventricle ejection fraction; MR = mitral regurgitation; PAPs = systolic pulmonary arterial pressure; TMG = mean transmitral gradient; TR = tricuspid regurgitation.

a Mild corresponds to a peak velocity >2.5 m/s according to the American Society of Echocardiography guidelines.

Acute evolution of flow biomarkers during TEER

Among the 65 patients included in the study, CT-ADP values were available in 52 patients (Figure 1). CT-ADP results are presented in Supplemental Figure 1. There was no significant difference in CT-ADP between the baseline and the first or last clip (129 [108-190] vs 136 [98-187] vs 135 [99-183] seconds, P = 0.180). However, the CT-ADP significantly decreased 1-hour post-TEER and remained stable at 24 hours compared to baseline (129 [108-190] vs 99 [82-130] vs 94 seconds [83-116] at baseline, 1 hour, and 24 hours, P < 0.001) (Figure 2A).Figure 2 Evolution of CT-ADP and vWF Levels After TEER

(A) Closure time with adenosine diphosphate (CT-ADP) significantly decreased at 1 hour and 24 hours after transcatheter edge-to-edge mitral valve repair (TEER) compared to baseline. (B) vWF:Act/vWF:Ag ratio only increased significantly at 1 hour post-TEER in the group of patients without residual MR (∗∗P < 0.01 compares vWF:Act/vWF:Ag ratio at 1 hour in patients with corrected MR vs patients with residual MR). Variables are presented as mean ± SD. MR = mitral regurgitation; vWF:Act/vWF:Ag = von Willebrand factor activity/antigen ratio.

Variables associated with residual MR

The vWF:Act/vWF:Ag ratio was used to document the evolution of the turbulent flow induced by MR correction. Figure 2B shows that patients with corrected MR had a significant increase of the vWF:Act/vWF:Ag ratio at 1-hour post-TEER vs baseline (+0.10 ± 0.02; P = 0.045). The ratio was significantly higher in patients with corrected vs residual MR (1.02 [0.99-1.12] vs 0.93 [0.85-1.01] IU/mL, P = 0.002). Variables associated with residual MR are listed in Table 3. Patients with residual MR were more likely to have lower vWF:Act/vWF:Ag ratio at 1-hour post-TEER and lower ΔvWF:Act/vWF:Ag. Multivariable models were performed, each adjusting for one of the following parameters: age, female sex, STS score, or O blood type (associated with lower vWF levels) (Supplemental Table 3). Only lower levels of vWF:Act/vWF:Ag ratio at 1-hour post-TEER remained significantly associated with residual MR.Table 3 Univariable Logistic Regressions Comparing Patients With and Without MR > Mild at 1 Month Post-TEER

Residual MR	OR (95% CI)	P Value	
 End-procedural CT-ADP (n = 52)	0.99 (0.98-1.00)	0.155	
1 h post-TEER			
 CT-ADP (n = 52)	0.99 (0.97-1.01)	0.208	
 vWF:Act/vWF:Ag (n = 49)	0.50 (0.27-0.81)	0.002a	
Δ (%)			
 ΔCT-ADP (n = 52)	1.00 (0.99-1.02)	0.641	
 ΔvWF:Act/vWF:Ag (n = 44)	0.94 (0.88-0.98)	0.021	
vWF:Act/vWF:Ag is presented with increments of 10.

P < 0.05 is considered to indicate statistical significance.

CT-ADP = closure time with adenosine diphosphate; MR = mitral regurgitation; TEER = transcatheter edge-to-edge mitral valve repair; vWF:Act/vWF:Ag = von Willebrand factor activity/antigen ratio.

a Also significant in multivariable models, each corrected for age, female sex, STS score, and O blood type (Supplemental Table 3).

Variables associated with clinical outcomes

Laboratory data at baseline, 1 hour after the procedure, and the percentage changes (Δ%) are displayed in Table 4. Among the 65 patients included in the study, 60 patients had both baseline and 1-hour postprocedural variables available (Figure 1). Baseline vWF:Act/vWF:Ag ratio was significantly higher in patients who had a clinical event during follow-up (respectively, 0.93 [0.87; 1.00] vs 1.04 [1.00; 1.23]; P = 0.003) (Table 4). Cox univariable analyses are shown in Table 5; patients with higher baseline vWF:Act/VWF:Ag ratio had an increased risk for all-cause mortality or HF hospitalizations after the procedure (HR: 13.96 [95% CI: 1.76-75.08], P = 0.005). Presence of TR > mild before the procedure was also associated with clinical events (HR: 3.43 [95% CI: 1.14-12.55], P = 0.038).Table 4 Laboratory Data in Patients With vs Without Clinical Event (All-Cause Mortality or HF Hospitalization)

	Free From Events (n = 43, 77.0%)	Clinical Events (n = 14, 23.0%)	P Value	
Baseline				
 CT-ADP, s	125 (108-194)	127 (104-145)	0.432	
 vWF:Act/VWF:Ag	0.93 (0.87-1.00)	1.04 (1.00-1.23)	0.003	
1 h post-TEER				
 CT-ADP, s	100 (86-126)	102 (87-132)	0.830	
 vWF:Act/VWF:Ag	1.00 (0.93-1.07)	1.00 (0.87-1.19)	0.874	
Δ% = 1 h post-TEER – baseline				
 ΔCT-ADP, %	−27 (−44 to −8)	−14 (−38 to −2)	0.183	
 ΔvWF:Act/VWF:Ag, %	6 (0-13)	0 (−11 to 2)	0.001	
HF = heart failure; other abbreviations as in Table 3.

Values are n (25th-75th percentiles).

P values compare results in the group free from events vs the group with clinical events. P < 0.05 is considered to indicate statistical significance.

Table 5 Variables Associated With All-Cause Mortality and Hospitalizations for Heart Failure

	Univariable Analysis	
HR (95% CI)	P Value	
Laboratory variables			
 Baseline CT-ADP	0.99 (0.98-1.00)	0.246	
 End-procedural CT-ADP	0.99 (0.98-1.00)	0.144	
 ΔCT-ADP	1.00 (0.99-1.03)	0.182	
 Baseline vWF:Act/VWF:Ag	13.96 (1.76-75.08)	0.005a	
 ΔvWF:Act/VWF:Ag	0.93 (0.88-0.97)	0.002a	
Clinical baseline variables			
 Age, years	1.01 (0.95-1.08)	0.836	
 Female sex	0.97 (0.30-2.82)	0.962	
 Hypertension	3.61 (0.72-65.64)	0.216	
 Dyslipidemia	0.89 (0.31-2.91)	0.841	
 COPD	1.55 (0.42-4.63)	0.460	
 Coronary artery disease	0.95 (0.33-2.79)	0.930	
 History of atrial fibrillation	0.82 (0.27-2.37)	0.715	
 eGFR	1.00 (0.98-1.03)	0.902	
 NT-proBNP	2.01 (0.56-7.75)	0.296	
 O blood type	0.67 (0.20-1.93)	0.466	
 STS Score MVR	1.11 (0.96-1.24)	0.093	
Pre-TEER echocardiographic variables			
 AR > mild	2.09 (0.57-6.24)	0.214	
 TR > mild	3.43 (1.14-12.55)	0.038	
 AS ≥ mild	0.58 (0.03-2.93)	0.602	
 PAPs	0.99 (0.96-1.02)	0.615	
Post-TEER echocardiographic variables			
 MR > mild	0.82 (0.27-2.35)	0.708	
 TMG >5 mm Hg	2.07 (0.68-5.97)	0.177	
Abbreviations as in Tables 1, 2, and 3.

P < 0.05 is considered to indicate statistical significance.

a Also significant in multivariable models, each corrected for age, female sex, STS score, O blood type, TR, and residual MR (Supplemental Table 4).

Evolution of biomarkers: Patients without clinical event after the procedure had a significantly higher increase in vWF:Act/vWF:Ag ratio (as estimated from percentage changes vs baseline) compared to patients who had a clinical event (ΔvWF:Act/VWF:Ag: 6% [0;13] vs 0% [-11;2], P = 0.001) (Table 4). Patients with a higher ΔvWF:Act/VWF:Ag ratio had a decreased risk for all-cause mortality or HF hospitalizations after the procedure (HR: 0.93 [95% CI: 0.88-0.97], P = 0.002) (Table 5). Residual MR > mild by echo evaluation was not associated with adverse outcomes (P = 0.708).

Multivariable models were performed, each adjusting for one of the following parameters: age, female sex, STS score, O blood type, tricuspid regurgitation, or residual MR (Supplemental Table 4). Baseline vWF:Act/vWF:Ag ratio remained significantly associated with increased risk of clinical events, along with the ΔvWF:Act/VWF:Ag ratio. Patients with higher baseline vWF:Act had also higher prevalence of coronary artery disease (P = 0.014) and a trend for more hypertension (P = 0.099) and dyslipidemia (P = 0.099).

Kaplan-Meier curves depicting freedom from all-cause mortality or HF hospitalizations at 1 year are illustrated in Figure 3. At baseline, patients who had an elevated vWF:Act/vWF:Ag ratio >1.015 were more likely to have clinical events during the follow-up (log-rank P < 0.001) (Figure 3A). The lack of improvement in the von Willebrand factor activity (ΔvWF:Act/VWF:Ag < 5.5%) after the procedure was associated with worse clinical outcomes (Log-rank P = 0.005) (Figure 3B). Threshold values were derived from receiver operating curves and Youden tests presented in Supplemental Table 5.Figure 3 Kaplan-Meir Curves Depicting Freedom From All-Cause Mortality or Heart Failure Hospitalizations

(A) Baseline levels of von Willebrand factor activity and antigen ratio (vWF:Act/vWF:Ag) ≤1.015 IU/mL vs >1.015 IU/mL. (B) Degree of improvement of vWF:Act/vWF:Ag ratio Δ ≥ 5.50% vs Δ <5.50%. MR = mitral regurgitation; vWF:Act/vWF:Ag = von Willebrand factor activity/antigen ratio.

Discussion

The main findings of our study are: 1) time-changes in CT-ADP evolution are not fast- or precise-enough to provide real-time monitoring of MR severity during TEER; 2) the vWF:Act/vWF:Ag ratio at 1-hour post-TEER was associated with residual MR at 1 month, but neither this metric nor residual MR assessed by echocardiography were associated with clinical outcomes at 1 year; and 3) 1-year clinical outcomes post-TEER were associated with baseline vWF:Act/vWF:Ag ratio and its improvement after the procedure.

The vWF is a glycoprotein released as a high molecular weight (HMW) multimers by endothelial cells and megakaryocytes.25 The vWF HMW multimers play an important role in hemostasis, particularly in platelet activation and aggregation.26 Valvular heart diseases such as aortic stenosis or MR are associated with high turbulent blood flow inducing the proteolysis of vWF HMW multimers and cause an acquired von Willebrand syndrome.8,9 The CT-ADP test is highly sensitive to defects in vWF HMW multimers and is increased in patients with turbulent blood flow.17,27 Van Belle et al have demonstrated that HMW multimers defects could resolve within minutes after percutaneous aortic valve procedures, significantly associated with paravalvular leak and mortality after the intervention.16,17 After a surgical mitral valve repair or replacement, CT-ADP was significantly decreased, and a postprocedural CT-ADP ≤121 seconds was associated with freedom of death or mitral valve surgery.8 Little data are available regarding the use of CT-ADP in patients undergoing TEER, with conflicting results.28,29 To our knowledge, our study is the first to describe the use of CT-ADP in a real-time procedural TEER frame. Our results suggested a normalization of CT-ADP 1 hour after the procedure. However, the dynamic changes in CT-ADP were not fast enough to enable real-time monitoring of the evolution of MR severity during the procedure. Moreover, this final CT-ADP value was not significantly linked to residual MR or clinical events. These results do not support the use of periprocedural CT-ADP monitoring in that setting. Although CT-ADP improvement has been shown as early as 5 minutes after flow correction,17 further improvement can be seen after a longer wait time. It is possible that our negative periprocedural CT-ADP results were related to an early measure (8 minutes after each clip); however, longer wait times are likely to result in procedural delays. Residual turbulent flow from MR and TR, as well as the hemodynamic effect of anesthesia, can also potentially interfere with the dynamic of CT-ADP improvement but could not be assessed in our study because of limited sample size.

The lack of association between residual MR and clinical events is in opposition with previous reports 3,30 and is likely related to our small sample size. This also highlights the difficulty to assess residual MR after TEER with echocardiography.6,31 Our results, however, showed that patients without significant improvement in the vWF activity 1-hour post-TEER vs baseline had more mortality and HF hospitalizations after the procedure. This metric is related to the decrease in turbulent flow, which considers the global improvement in MR rather than the final grade of MR (Central Illustration). Some patients can potentially benefit from TEER by going from very severe to mild or even moderate MR without being able to normalize their hemostatic parameters completely. In those patients, the amplitude of variation of MR and hemostatic markers might be potentially more important than the final MR grade or single biomarker value.Central Illustration Summary of the Mechanistic Impact of Turbulent Flow on vWF Multimers and Its Association With Outcomes in Patients Undergoing TEER

Von Willebrand factor (vWF) is a high molecular weight multimeric protein that is increased in patients with various comorbidities. An elevated von Willebrand factor activity/antigen ratio (vWF:Act/vWFAg) at baseline was found to be associated with mortality and hospitalizations for heart failure (HF) at 1 year of follow-up after transcatheter edge-to-edge mitral valve repair (TEER). In the presence of high shear stress induced by turbulent flow (mitral regurgitation), vWF multimers are cleaved by a metalloproteinase (ADAMST13), leading to a decrease in vWF:Act. Residual mitral regurgitation > mild after TEER was associated with lower values of vWF:Act/vWF:Ag ratio at 1-hour post-TEER. The percentage variation of vWF:Act/vWF:Ag ratio (Δ%) reflects the decrease in turbulent flow and was associated with mortality and hospitalization for HF after 1-year post-TEER. MR = mitral regurgitation.

Consistent with previous studies, our results demonstrated that an elevated baseline level of vWF activity expressed as vWF:Act/vWF:Ag ratio was associated with mortality and HF hospitalizations.11,13, 14, 15 Our results showed an association between elevated vWF:Act and coronary artery disease, which is consistent with previous reports.32 Hence, patients showing elevated vWF:Act/vWF:Ag ratio at baseline represent a population at risk for clinical events following TEER. Whether this marker can potentially help to refine preintervention evaluation will require validation in a larger cohort.

Study limitations

This was a single-center study with a limited number of patients and small number of clinical events. The statistical associations reported cannot be interpreted as cause-effect relationships. Residual MR was defined as any MR greater than mild; because of our small sample size, we could not perform analyses based on each MR grade (mild, moderate, and severe). Moreover, functional and primary MR were analyzed together in this exploratory work. The lack of association for residual MR and prognosis is in opposition with previous literature and likely related to limited power. Our results suggest that CT-ADP should not be used to monitor periprocedural MR acutely. The simultaneous presence of TR might also cause turbulence and influence our metrics. However, the influence of TR on vWF is attenuated due to the low-pressure system and the time before getting into the systemic circulation. Our study was not powered for this type of subanalysis. Because we did not control for the multiplicity in tests for secondary outcomes, the results should be taken with caution. Although our data suggest a potential value for baseline or serial (Δ) vWF metrics, those results will need validation in larger cohorts. To establish optimal cutoff values would need further validation in larger cohorts and require a predictive analysis.

Conclusions

This study does not support the use of intraprocedural CT-ADP to screen for residual MR during TEER. The vWF:Act/vWF:Ag ratio at 1-hour post-TEER was associated with residual MR at 1 month. The baseline vWF activity and its improvement following TEER (Δ) were associated with mortality and HF hospitalizations at 1 year after the procedure. These flow-dependent tests may have potential roles in classification and prognostication for patients undergoing TEER; however, those results will need validation in larger cohorts.PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: While CT-ADP variations were observed after TEER, intraprocedural measurements were not useful to monitor acute changes in MR. vWF:Act/vWF:Ag ratio at 1-hour post-TEER was associated with residual MR, and the degree of improvement of vWF activity following TEER was associated with mortality and HF hospitalizations at 1 year.

TRANSLATIONAL OUTLOOK: These flow-dependent tests may have potential roles in classification and prognostication for patients undergoing TEER and other valvular procedures but will require validation in larger cohorts.

Funding support and author disclosures

Ms Hadjadj and Dr Beaudoin are funded by Fonds de Recherche du Québec-Santé. This work was supported by Fondation de l’Institut Universitaire de Cardiologie et Pneumologie de Québec. Dr Rodés-Cabau holds the Research Chair “Fondation Famille Jacques Larivière” for the Development of Structural Heart Disease Interventions. Dr Pibarot has received institutional funding from 10.13039/100006520 Edwards Lifesciences , 10.13039/100004374 Medtronic , Pi-Cardia, and Cardiac Success for echocardiography core laboratory analyses and research studies in the field of interventional and pharmacologic treatment of valvular heart diseases, for which he received no personal compensation. Dr Beaudoin received research support from JAMP-Pharma, not related to the current work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Supplementary Data

Supplementary materials

Acknowledgment

The authors thank Serge Simard for statistical support.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

Appendix

For supplemental tables and a figure, please see the online version of this paper.
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