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Original research
Parameters associated with ventricular arrhythmias in mitral valve prolapse with significant regurgitation
  1. Aniek L van Wijngaarden,
  2. Marta de Riva,
  3. Yasmine Lisanne Hiemstra,
  4. Pieter van der Bijl,
  5. Federico Fortuni,
  6. Jeroen J Bax,
  7. Victoria Delgado,
  8. Nina Ajmone Marsan
  1. Cardiology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Nina Ajmone Marsan, Cardiology, Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands; n.ajmone{at}lumc.nl

Abstract

Objective Mitral valve prolapse (MVP) has been associated with ventricular arrhythmias (VA), but little is known about VA in patients with significant primary mitral regurgitation (MR). Our aim was to describe the prevalence of symptomatic VA in patients with MVP (fibro-elastic deficiency or Barlow’s disease) referred for mitral valve (MV) surgery because of moderate-to-severe MR, and to identify clinical, electrocardiographic, standard and advanced echocardiographic parameters associated with VA.

Methods 610 consecutive patients (64±12 years, 36% female) were included. Symptomatic VA was defined as symptomatic and frequent premature ventricular contractions (PVC, Lown grade ≥2), non-sustained or sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) without ischaemic aetiology.

Results A total of 67 (11%) patients showed symptomatic VA, of which 3 (4%) had VF, 3 (4%) sustained VT, 27 (40%) non-sustained VT and 34 (51%) frequent PVCs. Patients with VA were significantly younger, more often female and showed T-wave inversions; furthermore, they showed significant MV morphofunctional abnormalities, such as mitral annular disjunction (39% vs 20%, p<0.001), and dilatation (annular diameter 37±5 mm vs 33±6 mm, p<0.001), lower global longitudinal strain (GLS 20.9±3.1% vs 22.0±3.6%, p=0.032) and prolonged mechanical dispersion (45±12 ms vs 38±14 ms, p=0.003) as compared with patients without VA. Female sex, increased MV annular diameter, lower GLS and prolonged mechanical dispersion were identified as independent associates of symptomatic VA.

Conclusion In patients with MVP with moderate-to-severe MR, symptomatic VA are relatively frequent and associated with significant MV annular abnormalities, subtle left ventricular function impairment and heterogeneous contraction. Assessment of these parameters might help decision-making over further diagnostic analyses and improve risk-stratification.

  • mitral regurgitation
  • echocardiography
  • ECG/electrocardiogram

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Introduction

Mitral valve prolapse (MVP) is one of the most common valvular abnormalities with an estimated prevalence of 2%–3%,1 and can lead to severe mitral regurgitation (MR) requiring surgery. MVP is also known to be associated with ventricular arrhythmias (VA), from symptomatic premature ventricular contractions (PVCs), to ventricular tachycardia (VT) and sudden cardiac death (SCD).2–4 Initial studies related the occurrence of SCD to the presence of mitral valve (MV) flail and therefore specifically to severe MR.5 However, a malignant arrhythmic phenotype was later identified in patients with MVP and mild MR, when bileaflet prolapse was present together with T-wave inversion in the inferior ECG leads.2 6 More recently, mitral annular abnormalities such as mitral annular disjunction (MAD), have regained attention as another important characteristic associated with the occurrence of SCD and therefore part of the arrhythmic variant of MVP.7 8 The abovementioned studies however included specific cohorts of patients who experienced idiopathic SCD, highly selected based on their outcome. In turn, the prevalence of VA in patients with MVP is still largely unknown since published studies only included small populations, have used different definitions of MVP and severity of MR, and have assessed VA in diverse ways.9 10 Specifically, no studies have reported the prevalence of symptomatic VA in patients with MVP with significant MR, which represent the most common scenario in the clinical setting. The aim of our study was therefore to describe the prevalence of symptomatic VA, assessed in routine clinical practice, in patients who underwent MV surgery for significant MR due to MVP. Since it has been suggested that VA in MVP have a potential substrate in a primary diffuse myopathy process, and a trigger in the morphofunctional abnormalities of the valve apparatus,11 12 we also aimed at identifying specific clinical, ECG and echocardiographic parameters associated with VA, in order to better characterise the role of the left ventricle (LV) and the MV in the genesis of VA.

Methods

Study population

Patients with MVP, moderate-to-severe MR and preserved LV systolic function who underwent MV surgery at the Leiden University Medical Center between 2000 and 2018 were included and assessed for the presence of symptomatic VA before surgery. Preserved LV systolic function was defined as LV ejection fraction (LVEF) ≥55% based on current recommendations.13 The following exclusion criteria were applied: rheumatic valve disease, VA due to a demonstrated or possible ischaemic cause and unavailable preoperative transthoracic echocardiogram.

Patient and public involvement

Patients or the public were not involved in setting the research question or outcome measures, nor were they involved in developing plans for design or implementation of the study. They were not asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research.

Clinical characteristics

Demographic and clinical characteristics of patients were collected from the hospital information system (HIX 6.1; ChipSoft, Amsterdam, The Netherlands) and the patient electronic record used by the cardiology department (EPD-Vision; Leiden, The Netherlands). The following baseline information was obtained: age, sex, New York Heart Association (NYHA) classification, hypertension, diabetes, renal function, atrial and ventricular arrhythmias.

Electrocardiographic parameters

The most recent ECG prior to surgery was defined as baseline ECG and heart rate and rhythm, axis, PR, QRS, QT and QTc time, QRS configuration, ST-segment morphology and presence of inferior T-wave inversion were assessed.

Ventricular arrhythmias

Data on VA before surgery were collected from all available medical records. The presence of symptomatic VA was defined as: 1) symptomatic and frequent PVCs (Lown grade ≥2),14 2) non-sustained ventricular tachycardia (nsVT) defined as ≥3 consecutive beats at a rate >100 bpm up to a maximum duration of 30 s with spontaneous termination, 3) VT defined as ≥3 consecutive beats at a rate >100 bpm lasting >30 s and 4) ventricular fibrillation (VF).

Standard echocardiography

Standard transthoracic two-dimensional (2D) echocardiography was performed in all patients before surgery at rest in the left lateral decubitus position using commercially available ultrasound devices (Vivid 5, Vivid 7, System 5 and E9, GE Healthcare, Vingmed, Horten, Norway). Conventional 2D, M-mode, pulsed wave, continuous wave and colour Doppler images were acquired in parasternal and apical views, digitally stored and analysed offline using EchoPAC (V.112, V.202 and V.203 GE Medical Systems, Horten, Norway).

LV dimensions, mitral annular diameter, MAD and curling of the LV posterior wall were assessed in the parasternal long-axis view.13 The presence of MAD was defined as a separation between the left atrial (LA) wall at the level of the MV junction and LV free wall. A cut-off value of 5 mm was used to define the presence of MAD.15 Presence of curling of the LV posterior wall was identified by visual assessment as an outward movement of the MV annulus during systole.7 Apical two-chamber and four-chamber views were used to measure LV end-diastolic and end-systolic volumes and LVEF was calculated using Simpson’s biplane method.13 LA remodelling was quantified by LA end-systolic diameter in the parasternal long-axis view and maximum LA volume measured in systole in the two-chamber and four-chamber view indexed to body surface area (LAVI).13 Colour tissue Doppler imaging was used to obtain the mitral annular peak early velocity and peak systolic velocity at the lateral mitral annulus. MVP was diagnosed as leaflet displacement >2 mm beyond the mitral annulus in the long-axis plane16 and divided into Barlow’s disease and fibroelastic deficiency (FED). Barlow’s disease was defined as bileaflet prolapse or prolapse of more than one segment with excessive myxomatous tissue, elongated/ruptured chordae and severe annular dilatation.17 FED was defined as single segment prolapse mostly due to chordal rupture, with thin leaflets and/or thickening of the leaflet limited to the prolapsing segment.17 MV flail was defined as failure of leaflet coaptation with rapid systolic movement of the involved leaflet tip in the LA.18 MR was graded according to current guidelines using a multiparametric approach.19

Advanced echocardiography: speckle-tracking imaging

As previous studies suggested its value in patients with MVP,20–22 speckle tracking imaging was performed to better characterise global LV function by measuring global longitudinal strain (GLS), and to assess potential LV heterogenous contraction (early systolic vs postsystolic deformation) by measuring global prestretch index, postsystolic index and mechanical dispersion. The LV endocardial border was traced at end-systole in apical four-chamber, two-chamber and three-chamber views.13 The software provides LV GLS as the average value of peak systolic longitudinal strain across all three views using a 17-segment model and is presented as a negative value. However, in this study, absolute values of LV GLS are presented. The software also provides prestretch index defined as the ratio of early prestretch strain (as the maximal positive value of strain during early systolic contraction) to the difference between the early prestretch strain and the end-systolic strain. Also, postsystolic index was defined as the ratio of the difference between peak strain and end-systolic strain to the peak strain of the whole cardiac cycle. The prestretch and postsystolic indices were calculated for each segment and manually averaged for all 17 segments.20 Furthermore, mechanical dispersion was defined as SD of the time interval from onset of the QRS-complex to the peak longitudinal myocardial strain.22 Bull’s eye plots of GLS, prestretch and postsystolic indexes and mechanical dispersion values were obtained (figure 1).

Figure 1

Advanced echocardiographic measures in patients with mitral valve prolapse without (A) and with (B) ventricular arrhythmias. The coloured curves show the segmental longitudinal strain (and the dotted line the average for that view). The bull’s eye plots use a colour code for each of the measurements including longitudinal strain, PST, PSI and MD, while the global value for 17 segments is displayed in the upper right corner. In particular, the patient with VA (B) shows an impaired GLS, and high MD, PST and PSI. GLS, global longitudinal strain; LVEF, left ventricular ejection fraction; MD, mechanical dispersion; PSI, postsystolic index; PST, prestretch index; VA, ventricular arrhythmia.

Statistical analysis

Continuous variables are presented as mean±SD, when normally distributed and as median with IQR when not normally distributed. The Kolmogorov-Smirnov test and the Shapiro-Wilk test were used to assess for normality. Categorical variables are expressed as absolute numbers and percentages. Differences in clinical, ECG and echocardiographic characteristics between patients with and without VA were assessed using Student’s t-test, Mann-Whitney U test or χ2 test, when appropriate. Univariable binary logistic regression was used to identify parameters associated with presence of VA. From this analysis, statistically significant (p<0.05) or clinically relevant parameters were selected and introduced as covariates in the multivariable binary logistic regression model. ORs with 95% CIs are reported. C-statistic was used to evaluate the goodness-of-fit of the logistic regression models to evaluate which MV characteristic should be introduced in the final binary logistic regression model. The integrity of the final model was checked for collinearity (variance inflation factor <2.0) and outliers (Cook’s distance <<1.0). Statistical analysis was performed using SPSS V.23.0 (IBM, Armonk, New York, USA). For all tests, a two-sided p value <0.05 was considered to be statistically significant.

Results

Clinical characteristics

A total of 610 patients with MVP operated because of significant MR were included: 543 (89%) patients without VA and 67 (11%) patients with symptomatic VA. Of the 67 patients with symptomatic VA, 4% (3/67) had VF (out-of-hospital cardiac arrest), 4% (3/67) had sustained VT, 40% (27/67) had nsVT and 51% (34/67) had only symptomatic and frequent PVCs (see online supplemental table 1). Of note, some (16/67, 24%) of the patients with VF/VT/nsVT had also frequent PVCs or nsVTs. Of the 34 patients with only symptomatic and frequent PVCs, 44% patients had monomorphic and 29% had polymorphic PVCs (in 26% this information was not available). Of interest, three patients received an implantable cardioverter defibrillator before surgery due to a combination of syncope and nsVTs or inducible VT or VF during electrophysiological study. One of these patients received multiple ICD shocks due to VTs during follow-up.

Supplemental material

As shown in table 1 and figure 2, patients with symptomatic VA were significantly younger when they underwent surgery (62 (IQR 51–71) vs 66 (IQR 58–74) years, p=0.002), more often female (48% vs 34%, p=0.032) and more often diagnosed with Barlow’s disease (66% vs 45%, p=0.001) compared with patients without VA. In addition, patients with symptomatic VA had better renal function (estimated glomerular filtration rate 82 (IQR 71–103) vs 76 (IQR 61–90) mL/min/1.73 m2, p=0.009), probably related to their younger age. Patients with symptomatic VA were similar to patients without VA in terms of NYHA classification, comorbidities, history of atrial fibrillation and medication use.

Figure 2

Main significantly different variables between patients with and without symptomatic ventricular arrhythmias. Box plots of the following numerical variables: age at surgery, estimated glomerular filtration rate (eGFR), mitral valve (MV) annulus diameter, mitral annular disjunction (MAD), global longitudinal strain (GLS) and mechanical dispersion. MVP, mitral valve prolapse; VA, ventricular arrhythmias.

Table 1

Baseline clinical characteristics of patients with MVP with and without VAs

Electrocardiogram characteristics

Table 2 shows that patients with symptomatic VA had lower heart rates (63 (IQR 55–70) vs 68 (IQR 59–77) bpm, p=0.012) at the time of their baseline ECG and more often inferior T-wave inversion (24% vs 13%, p=0.014). However, there were no differences in heart rhythm, cardiac axis, conduction times, QRS configuration and ST-segment morphology between the two groups.

Table 2

Electrocardiographic characteristics of patients with MVP with and without VAs

Echocardiographic characteristics

Table 3 and figure 2 summarise the echocardiographic characteristics of patients with and without VA. LV dimensions and volumes, LVEF as well as LAVI did not significantly differ between the two groups. Patients with symptomatic VA had a larger MV annulus and more frequent MAD and curling of the LV posterior wall (p<0.001, p<0.001 and p<0.001, respectively) than patients without VA. When applying advanced echocardiographic measures, patients with symptomatic VA showed lower GLS (20.9%±3.1% vs 22.0%±3.6%, p=0.032), higher postsystolic index (3.71 (IQR 2.03–6.10)% vs 2.76 (IQR 1.53–4.53)%, p=0.014) and prolonged mechanical dispersion (45±12 ms vs 38±14 ms, p=0.003) as compared with patients without VA (figure 1).

Table 3

Standard and advanced echocardiographic characteristics of patients with MVP with and without VAs

Parameters associated with ventricular arrhythmias

A univariable binary logistic regression model was performed to assess which clinical, ECG and echocardiographic parameters were associated with the presence of symptomatic VA (online supplemental table 2). In addition to evaluate which parameter reflected best the MV characteristics, C-statistic analysis was performed testing four different models including the following variables: MV annular diameter, presence of MAD, occurrence of LV curling and the diagnosis of Barlow’s disease.

The first multivariable binary logistic regression model included the following parameters: age, sex, renal function and inverted T-waves in the inferior ECG leads (χ2=16.052; p=0.003). In the second model, several MV characteristics were added to the first model and based on C-statistics the model with the addition of MV annular diameter showed the best association with the presence of symptomatic VA (see online supplemental table 3) and improved the first model significantly (C-statistic=0.745, p=0.001, χ2=43.142, p<0.001). In the final model, advanced speckle tracking parameters such as GLS and mechanical dispersion were added to the previous model (C-statistic=0.817, p<0.001, χ2=48.129, p<0.001), and sex (women), a larger MV annular diameter, impaired GLS and prolonged mechanical dispersion were significantly associated with increased likelihood of developing VA (p=0.023, p<0.001, p=0.006 and p=0.023, respectively) (figure 3).

Figure 3

Final multivariate analysis to identify independent associates of symptomatic ventricular arrhythmias (VA). Forest plot of the different variables associated with the occurrence of symptomatic VA. GLS, global longitudinal strain; MD, mechanical dispersion; MV, mitral valve.

Discussion

The current study explored the prevalence of symptomatic VA in a large population of patients with MVP and significant MR undergoing surgery, and showed that women, mitral annular abnormalities, impaired GLS and increased mechanical dispersion are independently associated with the presence of symptomatic VA (figure 4).

Figure 4

Clinical and echocardiographic parameters associated with the occurrence of symptomatic ventricular arrhythmias. In patients with moderate-to-severe or severe mitral regurgitation due to mitral valve prolapse, female sex, mitral annular characteristics (especially mitral valve annulus diameter), left ventricular global longitudinal strain and mechanical dispersion are independently associated with the occurrence of symptomatic ventricular arrhythmias. Presence of T-wave inversion in the inferior ECG leads are also known to be associated with ventricular arrhythmias in these patients.

MVP: the arrhythmic phenotype

Previous studies have described the occurrence of malignant VA in patients with MVP and identified potential risk factors such as female sex, younger age, inferior T-wave inversion and bileaflet prolapse.2 6 More recently, mitral annular abnormalities, such as MAD, and presence of myocardial fibrosis at the level of the papillary muscles were also associated with the arrhythmic phenotype of MVP.7 8 However, the results of these studies were based on selected populations of patients who experienced idiopathic SCD or who had mainly trivial or mild MR.9 10 23 In turn, data on the prevalence of symptomatic VA in patients with MVP with significant MR are very limited, despite being these patients the most frequently referred for cardiological evaluation. The present study included a large cohort of consecutive patients with MVP referred for surgery, and using the findings of screening based on clinical indication, a relatively high (11%) prevalence of symptomatic VA was noted. This observation highlights the clinical relevance of VA in patients with MVP because of possible dramatic consequences such as SCD (with an estimated occurrence of 0.2%–1.9%).24 Frequent PVCs can in fact be very invalidating for these patients, leading to significant symptoms which are difficult to interpret by the treating physician as purely related to the severity of MR or as a distinct problem. Therefore, the clinical challenge is whether to primarily treat the MR to resolve also the PVCs-related symptoms or to start specific treatment including anti-arrhythmic drugs or even consider ablation. However, whether PVCs are resolved after surgery, or whether anti-arrhythmic drugs or ablation procedures are effective in these patients is largely unknown. Furthermore, although the published literature is scarce, complex PVCs are often observed in patients with MVP experiencing more malignant arrhythmias (probably as trigger to more sustained arrhythmias) and might be considered in some cases an indication for an implantable cardioverter defibrillator. With the current study, we could not provide the answers to these clinical questions, but a better understanding of which are the possible determinants of symptomatic VA in patients with MVP, including valvular morphofunctional characteristics and myocardial function abnormalities, maybe be important to guide further diagnostic testing and overall patient management.

Associates of VA in patients with MVP

Although the mechanisms of VA in patients with MVP are still not fully understood, previous studies have suggested that VA may be the result of a valvular trigger acting on a pathological myocardial substrate, such has hypertrophy or fibrosis.3

The first studies evaluating PVC morphologies in patients with MVP showed that the dominant form was originating most frequently from the papillary muscles,25 suggesting the hypothesis of increased mechanical traction on the papillary muscles by the prolapsing valve (trigger), which would induce the PVCs, and potentially also malignant VA when the papillary muscles develop myocardial fibrosis.12 Recent studies using cardiac MRI together with results of autopsies of patients with MVP suffering SCD demonstrated the presence of focal myocardial fibrosis of the papillary muscles and fibrosis in the basal LV adjacent to the MV in a large proportion of these patients.24 26 However, electrophysiological studies demonstrated that ventricular ectopy in patients with MVP originate from the MV apparatus and frequently from other regions such as the outflow tracts.11 These observations suggest that the myocardial substrate for VA might also be represented by a diffuse myopathy rather than only focal myocardial alterations.27 Initial studies have supported this hypothesis showing in these patients an increased myocardial interstitial fibrosis.26 Echocardiographic parameters which are able to detect subtle impairment of LV function and heterogeneous ventricular contraction, might also reflect diffuse and focal myocardial fibrosis and be able to identify patients with MVP at higher risk of VA. LV mechanical dispersion, which has been associated with VA in dilated and hypertrophic cardiomyopathy and in ischaemic heart disease, was also shown to be increased in a small selected group of patients with MVP and VA.22 28 29 In the current study with a large cohort of patients with MVP, LV mechanical dispersion and GLS were both associated with VA, showing incremental value in the risk prediction model which also included previously proposed risk factors such as age, sex and inverted T-wave on the inferior leads. Our findings further support the importance of identifying subtle myocardial alterations in these patients in order to improve patient management and risk-stratification.

The valvular trigger acting on the myocardial substrate might be represented by the (acute) volume overload of MR but most probably by the long-standing morphofunctional abnormalities of the MV related to MVP.12 The presence of a bileaflet prolapse as a known potential risk factor for VA2 was confirmed in our cohort where Barlow’s disease was associated with VA. More recent studies have focused on MAD as predictor of VA and specifically in patients without significant leaflet prolapse or MR and with normal LVEF8; they showed that a MAD length of >4.8 mm was associated with myocardial fibrosis and a length of >8.5 mm with a higher risk of arrhythmic events.15 In our study, the prevalence of MAD in a cohort of operated patients with MVP was similar compared with a recent published study by Mantegazza et al 30; however, prevalence of MAD varies among studies probably because of differences in patient populations and definition of MAD. In addition, our analysis showed that MAD was clearly associated with VA, but not as robustly, a fact which is probably related to a different and less selected patient population. In turn, MV annular dilatation was the most relevant parameter, probably by itself reflecting the different potential triggers arising from the MV apparatus, such as MAD and annular dysfunction (curling), extent of prolapse and chordal elongation and finally severity of MR and LV dilation.

Overall, the present study proposed novel parameters associated with VA in patients with MVP, which might help identify which patients deserve additional analyses to clarify the arrhythmic burden (Holter, exercise test, etc), unravel their myocardial substrate (cardiovascular magnetic resonance, genetic testing, ischaemia detection) and decide eventually on close surveillance and therapeutic strategies.

Study limitations

Several limitations of our study should be mentioned. First, although a large population of patients with MVP was included, still a relatively small group of patients had symptomatic VA, which limited the possibility to include all potential predictors of VA in our multivariate models. Second, the evaluation of symptomatic VA was performed retrospectively based on clinical indication, meaning that the prevalence of VA was probably underestimated; even taking this into account, our study so far has the largest patient population in this setting. Similarly, due to the retrospective analysis, detailed information about VA morphology was limited. Third, cardiovascular magnetic resonance data to evaluate the presence of myocardial fibrosis were not systematically available in our patients and therefore correlation with the echocardiographic parameters was not possible. Finally, the localisation of the PVCs and the occurrence of arrhythmias after surgery was not systematically assessed and therefore further prospective studies are needed to clarify the localisation of VA and the effect of surgery on VA during follow-up.

Conclusion

In patients with moderate-to-severe or severe MR due to MVP, female sex, mitral annular characteristics (especially MV annulus diameter), LV GLS and mechanical dispersion are independently associated with the occurrence of symptomatic VA. These clinical and echocardiographic parameters may represent important markers to help identify which patients should undergo additional diagnostic testing and close surveillance.

Key questions

What is already known on this subject?

  • Mitral valve prolapse (MVP) is known to be associated with ventricular arrhythmias (VA) and potential risk factors have been identified such as female sex, younger age, inferior T-wave inversion, bileaflet prolapse and the occurrence of mitral annular disjunction.

What might this study add?

  • This study shows that VA are relatively frequent in patients with MVP and severe mitral regurgitation (until now not specifically investigated).

  • It also identifies additional associates of VA such as mitral valve annular abnormalities, lower global longitudinal strain and prolonged mechanical dispersion.

How might this impact on clinical practice

  • Identification of novel parameters associated with VA in MVP might help patient management and particularly to identify which patients deserve additional analyses to clarify the arrhythmic burden (Holter, exercise test, etc) and their myocardial substrate (MRI, genetic testing, ischaemia detection).

References

Footnotes

  • Contributors All authors contributed to the conception and the design of the study. ALvW, MdR, YLH, PvdB and NAM contributed to acquisition of the data. ALvW, FF and NAM analysed the data, all authors contributed to interpretation of the data. Drafting of the manuscript was done by ALvW and NAM, the manuscript was critically revised by MdR, FF, PvdB, JJB and VD. Finally, all authors gave final approval and agreed to be accountable for all aspects of the work ensuring integrity and accuracy.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests The Department of Cardiology received unrestricted research grants from Abbott Vascular, Bayer, Bioventrix, Biotronik, Boston Scientific, Edwards Lifesciences, GE Healthcare and Medtronic. VD received speaker fees from Abbott Vascular, Edwards Lifesciences, GE Healthcare and Medtronic. NAM received speakers fees from Abbott Vascular and GE Healthcare. JJB received speaker fees from Abbott Vascular. The remaining authors have nothing to disclose.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Institutional Review Board and Medical Ethical Committee of the Leiden University Medical Center. The study complies with the Declaration of Helsinki. The Institutional Review Board and Medical Ethical Committee waived the need of written informed consent for this retrospective analysis of clinical data acquisition.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request.

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