Author + information
- Received July 27, 2014
- Revision received October 15, 2014
- Accepted October 23, 2014
- Published online March 1, 2015.
- Robert Schueler, MD∗,
- Can Öztürk, MD∗,
- Jan Arne Wedekind, MD†,
- Nikos Werner, MD∗,
- Florian Stöckigt, MD∗,
- Fritz Mellert, MD‡,
- Georg Nickenig, MD∗ and
- Christoph Hammerstingl, MD∗∗ ()
- ∗Heart Centre Bonn, Department of Cardiology, University of Bonn, Bonn, Germany
- †Asklepios Children's Hospital Sankt Augustin, Stankt Augustin, Germany
- ‡Heart Centre Bonn, Department of Cardiac Surgery, University of Bonn, Bonn, Germany
- ↵∗Reprint requests and correspondence:
Priv. Doz. Dr. med. Christoph Hammerstingl, Medizinische Klinik und Poliklinik II, Universitätsklinikum Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Objectives The purpose of this study was to investigate the persistence rates of iatrogenic atrial septal defect (iASD) after interventional edge-to-edge repair with serial transesophageal echocardiography examinations and close clinical follow-up (FU).
Background Transcatheter mitral valve repair (TMVR) with the MitraClip system (Abbott Vascular, Abbott Park, Illinois) is a therapeutic alternative to surgery in selected high-risk patients. Clip placement requires interatrial transseptal puncture and meticulous manipulation of the steerable sheath. The persistence of iASD after MitraClip procedures and its clinical relevance is unknown.
Methods A total of 66 patients (76.7% male, mean age 77.1 ± 7.9 years) with symptomatic mitral regurgitation (MR) at prohibitive surgical risk (EuroSCORE II 10.1 ± 6.1%) underwent MitraClip procedures and completed 6 months of FU.
Results Transesophageal echocardiography after FU showed persistent iASD in 50% of cases. Patients with iASD did not significantly differ from patients without ASD concerning baseline characteristics, New York Heart Association functional class, severity of MR, and acute procedural success rates (p > 0.05). When comparing procedural details and hemodynamic measures between groups, MitraClip procedures took longer in patients without iASD (82.4 ± 39.7 min vs. 68.9 ± 45.5 min; p = 0.05), and echocardiography after FU showed less decrease of systolic pulmonary artery pressures in the iASD group (−1.6 ± 14.1 mm Hg vs. 9.3 ± 17.4 mm Hg; p = 0.02). Clinically, patients with iASD presented more often with New York Heart Association functional classes >II after FU (57% vs. 30%; p = 0.04), showed higher levels of N-terminal pro-brain natriuretic peptide (6,667.3 ± 7,363.9 ng/dl vs. 4,835.9 ± 6,681.7 ng/dl; p = 0.05), and had less improvement in 6-min walking distances (20.8 ± 107.4 m vs. 114.6 ± 116.4 m; p = 0.001). Patients with iASD showed higher death rates during 6 months (16.6% vs. 3.3%; p = 0.05). Cox regression analysis found that only persistence of iASD (p = 0.04) was associated with 6-month survival.
Conclusions The persistence rate of 50% iASD after MitraClip procedures is considerably high. Persistent interatrial shunting was associated with worse clinical outcomes and increased mortality. Further studies are warranted to investigate if persistent interatrial shunting is the mediator or marker of advanced disease in these patients.
Transcatheter mitral valve repair (TMVR) has been developed as a therapeutic alternative to mitral valve (MV) surgery for symptomatic patients with relevant mitral regurgitation (MR) at prohibitive surgical risk. Interventional edge-to-edge repair with the MitraClip system (Abbott Vascular, Abbott Park, Illinois) has proven to be safe and effective for the reduction of MR in different patient cohorts with either functional mitral regurgitation (FMR) or degenerative mitral regurgitation (DMR) valve disease (1,2), and this technique has been widely adapted for clinical use, with more than 13,000 documented implants worldwide.
In clinical practice, TMVR with the MitraClip is mainly used to reduce FMR in end-stage heart failure patients with either dilated or ischemic cardiomyopathy (3–6). In this high-risk population, acute procedural success rates of up to 99% with significant MR reduction were reported (7), followed by symptomatic improvement in approximately 80% of cases.
Nevertheless, TMVR with the MitraClip is still an evolving technique, and factors predicting clinical outcomes after technically-successful clip implantation are not well defined. Cardiologists are facing a complex procedure, and clip placement requires venous groin access, interatrial transseptal puncture, and advancement of a 21-F (7.2 mm) steerable sheath into the left atrium. Despite increasing knowledge on specific procedural characteristics and technical aspects of TMVR, the persistence rate of iatrogenic atrial septal defects (iASDs) after MitraClip procedures is unknown. Furthermore, the effect of iASD on clinical outcomes in patient cohorts with advanced stages of chronic heart failure has not been systematically investigated.
In this prospective, single-center study, we included consecutive patients undergoing TMVR with the MitraClip system. All patients underwent close clinical follow-up (FU) and echocardiography after 6 months to determine functional results after TMVR and clinical outcomes.
Symptomatic patients with relevant DMR grade 3 to 4+ were evaluated for TMVR or surgery. Patients with FMR and mitral regurgitation grade 2+ were considered for MR treatment when having an effective regurgitation orifice area of >20 mm2, New York Heart Association (NYHA) functional class III to IV, concomitant atrial fibrillation, and/or elevated pulmonary pressure despite optimized medical and device therapy (8). TMVR was planned for patients if the heart team recommended against open-heart surgery.
The study was approved by local ethics committee and in concordance with the Declaration of Helsinki, and all patients had to provide written informed consent before study inclusion.
Echocardiography and FU assessment
Echocardiographic assessment before and after TMVR was done following current recommendations and guidelines, including comprehensive transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) (9,10). Severity of MR was graded after determination of proximal isovelocity surface area, effective regurgitation orifice area, as well as vena contracta width and regurgitant volume (8,9). According to the EVEREST (Endovascular Valve Edge-to-Edge REpair Study) (7) and the recommendations of the European Society of Cardiology (9), we established an institutional standard categorizing the severity of MR following a scale ranging between 1 and 4+: grade 1 defines “mild,” 2 refers to “moderate,” 3 stands for “moderate to severe,” and 4 stands for “severe” MR. TEE and TTE were performed with a commercially-available echocardiographic system (iE 33, Philips Medical Systems, Andover, Massachusetts) and echocardiography probes (X5-1, X7-2t) allowing acquisition of 2- and 3-dimensional datasets. For the determination of iASD during FU, the interatrial septum was visualized in multiple angulations with and without color Doppler to identify visible structural defect or atypical interatrial Doppler flow (Figure 1).
Different experienced echocardiographers obtained procedural (C.H., F.S.) and FU (R.S., C.Ö.) images. The echocardiographer who performed FU evaluation was blinded to procedural outcomes and the patients’ characteristics. Trained study nurses carried out clinical FU evaluation, unattended by the interventionalists or procedural echocardiographer.
Interventional edge-to-edge repair of MR
TMVR using the MitraClip system has been described in detail previously (7). During the MitraClip procedure, severity and acute changes of MR were assessed as supposed by Foster et al. (11) and Wunderlich and Siegel (12). We defined acute procedural success as a reduction of MR by at least 1 grade, with a residual MR <2+. The number of clips that were implanted to reach procedural success was left to the discretion of the treating physician. Before clip release, echocardiography was performed to exclude clinical relevant MV stenosis (mean pressure gradient >5 mm Hg). Clinical success was defined by a decrease of ≥1 NYHA functional class during FU.
Normal distribution of continuous variables was examined using the Kolmogorov-Smirnov test. Comparisons between FMR and DMR groups at 6 months were done using analysis of covariance for continuous variables. Further comparisons were performed with using the Student 2-sample t test or Mann-Whitney U test depending on the distribution of data. For categorical data, the Fisher exact test or chi-square test was calculated. Continuous data were expressed as mean ± SD or median (with interquartile ranges) where applicable. The 2-tailed p values were calculated, and p < 0.05 was considered to be significant. The cumulative survival plot in relation to iASD was estimated by the Kaplan-Meier method. Survival in groups was compared using the log-rank test. Cox regression was performed to analyze the influence of single variables on 6-month mortality. Variables were chosen for Cox regression if they have been shown independently to increase heart failure–related mortality in MR patients. Due to the relatively low event rate at 6-month FU, multivariate analysis was not performed.
Intraclass correlation coefficients for absolute agreement was used to assess method agreement, with good agreement defined as >0.80. For the assessment of intraobserver reliability, 20 randomly-chosen patients from each group (iASD and no iASD) were analyzed by the same investigator twice (C.H.), then by a second investigator (R.S.) who was blinded to the results of the first investigator, to determine interobserver variability. Mean values and SDs between the measurements were obtained, and absolute agreement among the observations was calculated using intraclass correlation coefficient analysis.
Statistics were performed using the SPSS for Windows PASW statistic, version 22.214.171.124 (SPSS Inc., Chicago, Illinois) and MedCalc statistical software version 126.96.36.199 (MedCalc, Mariakerke, Belgium).
Baseline data and procedural outcomes
From February to December 2013, 66 consecutive patients (age 77.1 ± 7.9 years, 76.7% male, EuroSCORE II 10.1 ± 6.1%, 73.3% FMR) (Table 1) underwent TMVR with the MitraClip system at our institution and completed the 6-month FU procedure including TTE and TEE. The patients underwent MitraClip procedures primarily for the treatment of advanced stages of symptomatic heart failure, with 96.7% of patients in NYHA functional class III or IV and 51% of patients with documented left ventricular ejection fraction (LVEF) <35%. The procedure was successfully completed in 65 patients (98.5%), with implantation of >1 clip in 40% of cases. Mean procedural time was 75.8 ± 42.8 min (interquartile range: 26 to 221 min) with a documented fluoroscopy time of 24.5 ± 17.7 min (interquartile range: 5 to 100 min) (Table 2). In 1 patient, TMVR was aborted because of relevant MV stenosis occurring after clip closure; in this case, the system was retrieved uneventfully without post-procedure changes in MR. Thereafter, the patient was treated conservatively, because of prohibitive surgical risk.
In-hospital, 30-day, and 6-month outcomes are shown in Table 2. The majority of patients improved significantly after FU, with documented decrease of ≥1 NYHA functional class in 81.6% of cases.
Echocardiographic measures after FU
Echocardiography after 6 months revealed sustained reduction of MR <2+ in 91.6% of patients (Figure 2A). Concomitantly, we found a significant reduction in estimated systolic pulmonary arterial pressure (sPAP) (43.6 ± 14.1 mm Hg vs. 35.6 ± 16.6 mm Hg; p = 0.02) and left ventricular (LV) end-diastolic volume (195.1 ± 77.2 ml vs. 176.9 ± 84.7 ml; p = 0.03) in the overall cohort, without significant changes in LV end-systolic volume (121.7 ± 69.4 ml vs. 109.8 ± 73.3 ml; p = 0.1) or LVEF (41.2 ± 15.8% vs. 42.3 ± 14.5%; p = 0.7).
Mean MV pressure gradients were significantly increased after MitraClip procedures (1.5 ± 0.8 mm Hg vs. 3.4 ± 1.5 mm Hg; p = 0.001) without incidence of significant MV stenosis (Online Table 1).
Persistence of iASD and comparison of baseline characteristics
Persistence rate of iASD as documented with TEE was 50%, with measured maximal and minimal diameters of 4.3 ± 1.7 mm (interquartile range: 1.1 to 7.9 mm) and 3.8 ± 2.1 mm (interquartile range: 1.2 to 7.1 mm), respectively. In 2 of 33 cases (6%), TEE showed spontaneous right-to-left shunt via iASD. When comparing groups separated by persistence of iASD after 6 months, we found no significant differences concerning baseline characteristics (Table 1), acute procedural success rates, MV gradient, and amount of residual MR after clip placement (Table 2). TMVR took longer in patients with iASD (82.4 ± 39.7 min vs. 68.9 ± 45.5 min; p = 0.05), which was associated with longer radiation times (30.5 ± 20.6 min vs. 18.6 ± 11.9 min; p = 0.05).
We found no significant differences between groups in baseline functional parameters, severity of MR, or measured sPAP. Patients with persistent iASD had larger basal (5.1 ± 0.8 cm vs. 4.6 ± 0.8 cm; p = 0.01) and midventricular (3.7 ± 0.8 cm vs. 3.3 ± 0.7 cm; p = 0.03) right ventricular diameters at baseline (Table 3).
Association of iASD with echocardiographic measures after FU
When separating patients according to presence of iASD after 6 months, we found no significant differences in residual MR, MV gradients, or LV diastolic volume and function. In concordance with the obtained baseline measurements, right ventricular diameters remained larger in iASD patients but did not significantly differ from baseline (Online Table 1).
Interestingly, only patients without iASD experienced significant reductions in LV end-diastolic (198.4 ± 80.2 ml vs. 174.4 ± 94.1 ml; p = 0.04) and end-systolic (122.7 ± 74.1 ml vs. 103.9 ± 79.3 ml; p = 0.05) volumes during FU, without significant changes in measured LV function (LVEF: 42.1 ± 16.9% vs. 44.9 ± 14.7%; p = 0.3) (Table 4).
The decrease in echocardiographically-measured sPAP was significantly different between groups (Figure 3A); only patients without iASD experienced a significant decrease of measured sPAP (43.47 ± 15.1 mm Hg vs. 32.5 ± 11.9 mm Hg; p = 0.03), whereas sPAP remained unchanged in the iASD group (42.5 ± 13 mm Hg vs. 44.1 ± 19.2 mm Hg; p = 0.8) (Online Table 1). Furthermore, right atrial areas increased significantly in the iASD group during FU (28.9 ± 7.4 cm2 vs. 34.2 ± 11.7 cm2; p = 0.002) with a concomitant decrease in left atrial volumes (162.5 ± 63.3 ml vs. 139.1 ± 47.6 ml; p = 0.04) (Table 4). In patients without ASD, there were no significant changes in right and left atrial dimensions (p > 0.05).
Association of iASD with functional outcomes and survival
Patients with iASD experienced a significantly lower increase in 6-min walking distances compared with patients without iASD (20.8 ± 107.4 m vs. 114.6 ± 116.4 m; p = 0.001) (Figure 3B) and showed higher levels of N-terminal pro-brain natriuretic peptide 6 months after clip placement (6,667.3 ± 7363.9 ng/dl vs. 4,835.9 ± 6,681.7 ng/dl; p = 0.05).
Overall, 57% of patients with iASD remained in functional NYHA functional class >II compared with 30% of patients without iASD (p = 0.04) (Figure 2B).
Survival rates were significantly different between groups: 6 patients (16.6%) with iASD died during FU compared with 1 patient (3.3%) in the groups without iASD (log rank p = 0.05) (Figure 4).
After Cox regression analysis, only the presence of iASD was associated with survival during FU (Table 5).
The echocardiographic FU evaluation had a good reproducibility. We found a good intraclass and interclass absolute agreement, with all correlation coefficients ranging above 0.8 (Table 6).
To our knowledge, this is the first study investigating the persistence rates of iASD after interventional edge-to-edge repair with serial TEE examinations and close clinical FU. Following our results, the persistence rate of iASD after MitraClip procedures with transseptal left atrial access was high (50%). This finding is clinically important because persistent interatrial shunt was associated with worse hemodynamic and clinical development after TMVR and—more importantly—with an increased probability for all-cause death.
The reasons for these unfavorable outcomes remain unclear at the current stage. As a matter of fact, at-risk patients need special care, because the hemodynamic effects of interatrial shunt defects in patients with predominantly advanced stages of chronic heart failure have not been systematically investigated.
Persistence rates of iASD after cardiac interventions with transseptal access
Limited data are available on persistence rates and predictors for iASD after different cardiac procedures. According to our own experiences, the underlying pathomechanism combines technical, interventional, and patient-derived factors. We investigated 42 patients undergoing pulmonary vein isolation with either single (n = 27) or double (n = 15) transseptal 8-F catheters. Factors associated with iASD persistence after FU were the use of a single transseptal sheath demanding more extensive interatrial movement (p = 0.01) and the prevalence of pulmonary hypertension before pulmonary vein isolation (p = 0.05) (13). More recently, Sieira et al. (14) described a 12-month persistence rate of 20% for iASD in 39 patients undergoing pulmonary vein isolation with considerably larger 15-F transseptal sheaths.
When regarding other structural/transseptal interventions, iASD persisted in 18% of patients undergoing mitral valvuloplasty with dilation of the interatrial septum by using an 8-mm balloon (15) and in 7% of patients after left atrial appendage closure with a 12-F transseptal sheath (16).
At this time, only 1 study has investigated persistence rates for iASD after MitraClip implantations with TEE. Saitoh et al. (17) examined 10 patients 1 month after MitraClip implantation and found a 90% iASD persistence rate. In our study, iASD persistence was considerably less, which can be explained by the fact that the FU period was relevantly longer, allowing for further defect healing. We did not compare intraprocedural iASD diameters of patients separated by iASD persistence.
When putting our findings in context with the available evidence, the iASD persistence rate of 50% seems caused by predominantly 2 factors: 1) TMVR with the MitraClip requires extensive movement of a large transseptal sheath (21-F, 7.3 mm); and 2) local trauma increases with rising procedural time in the iASD group.
Clinical effect of interatrial shunt defects in a “MitraClip population”
Available evidence is sparse investigating hemodynamic effects and clinical consequences of iASD after TMVR with the MitraClip systems. Theoretically, iASD with bidirectional interatrial shunt can provoke paradoxical embolism and worsen clinical symptoms of heart failure due to volume overload. However, Hoffman et al. (18) found evidence for beneficial hemodynamic consequences of iASD in 28 patients undergoing MitraClip procedures caused by acute left atrial pressure relief. Our findings on reverse changes of right and left atrial dimensions in patients with iASD support this hypothesis. However, according to the clinical outcomes in our cohort after 6 months, persistent right atrial volume overload seems to not be beneficial in this patient group.
Conversely, several case reports have been published describing detrimental clinical effects of iASDs in selected patients with predominantly advanced stages of chronic heart failure. In all cases, symptoms abated after interventional iASD closure, supporting the hypothesis of the iASD being the underlying cause of disease (19,20). Sirker et al. (20) found increased oxygen requirements in a patient with persistent iASD after transseptal MV surgery; the patient improved immediately after iASD device closure. Huntgeburth et al. (19) found worsening of right-heart failure related symptoms in 3 patients after MitraClip procedures, and all patients were treated successfully with interventional defect closure (19).
When adding these findings with the available evidence on procedural shunt defects, a negative hemodynamic or clinical effect of iASD was never shown in larger cohorts of patients undergoing pulmonary vein isolation (14,21), mitral valvuloplasty (22) or LAA closure (16).
What makes the difference in MitraClip patients?
First, MitraClip therapy is primarily performed in selected high-risk patients who receive TMVR for the treatment of advanced stages of symptomatic chronic heart failure accompanied by reduced LV function and increased LV end-diastolic pressures (6,23–25). Second, the atrial defect size after TMVR is considerably larger (17), increasing interatrial shunt volumes. Third, persistence rates are high due to extensive movement of a large sheath during complex procedures. The acute and persistent hemodynamic effects of interatrial shunting in this vulnerable population have not yet been investigated. In line with an increasing number of published case reports in this field, there is growing evidence that iASD might negatively affect clinical patient outcomes.
We investigated only a small number of patients who underwent TMVR procedures with the MitraClip system, and other groups should confirm our findings independently. Ideally, the hemodynamic effects of interatrial shunt defects would be determined invasively at baseline and during FU. At this stage, it remains unclear whether iASD is the reason for or effect of unfavorable hemodynamic and clinical outcome measures. We report the findings of a single-center study and cannot exclude that procedural details and interventional steps differ significantly from other sites, which might have a relevant effect on iASD persistence rates. We, furthermore, cannot exclude a documentation bias of clinical outcome measures, because statistical testing for reliability was not performed. However, in every patient, clinical assessment was performed by trained nurses, and the plausibility of the results was checked by experienced physicians. Additionally, clinical measures were correlated with quantitative parameters on functional capacity (N-terminal pro-brain natriuretic peptide, 6-min walk distance).
The iASD persistence rate of 50% after MitraClip procedures is considerably high. Persistence of interatrial shunting was associated with worse clinical outcomes and increased mortality rates. Further studies are warranted to investigate if iASD is a mediator or marker for advanced stages of chronic heart disease in these patients.
For supplemental tables, please see the online version of this article.
Dr. Mellert has served as a proctor for Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Schueler and Öztürk contributed equally to this work.
- Abbreviations and Acronyms
- degenerative mitral regurgitation
- functional mitral regurgitation
- iatrogenic atrial septal defect
- mitral regurgitation
- New York Heart Association
- transesophageal echocardiography
- transcatheter mitral valve repair
- transthoracic echocardiography
- Received July 27, 2014.
- Revision received October 15, 2014.
- Accepted October 23, 2014.
- 2015 American College of Cardiology Foundation
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