Background: Limited data are available on the increase in cardiac troponin after transcatheter closure of interatrial septal defects, and the mechanism is not fully understood. The aim with the study was to examine retrospectively whether transcatheter closure of the interatrial septum leads to myocardial injury, and to determine the mechanism. Methods: Troponin T (TnT) serum concentrations were determined before and 1 day after transcatheter closure of an atrial septal defect (ASD) or patent foramen ovale (PFO) in a retrospective study in adults. Fifty-one patients were included, 36 ASD and 15 PFO (female/male 35/16), mean age 52 ± 16 y (range 17–80 y). Results: An increase in TnT was observed 1 day after the procedure (p = 0.000) in 44 patients (92%). The increase in TnT was significantly correlated to the size of the ASD (r = 0.424, p = 0.010), as well as to the size of the implanted ASD device (r = 0.542, p = 0.001), and the duration of the ASD intervention (r = 0.348, p = 0.035). In cases of PFO, the increase in TnT was not correlated with the size of the PFO or the PFO device, or the duration of the intervention. No correlations were found between the increase in TnT and the patient’s age, body weight or body surface area. Conclusions: Transcatheter closure of the interatrial septum causes an increase in TnT indicating a minor and clinically insignificant myocardial injury. The findings indicate that mechanical trauma caused by inserting the ASD device may play an important role in this elevation. The impact of the size of the device on the degree of TnT elevation reflects the amount of myocardium affected by the device. Trial registration: NCT03099967. Registered 4 April 2017, retrospectively registered. Keywords: Congenital heart disease, Atrial septal defect, Patent foramen ovale, Transcatheter closure, Troponin T Background The aim of this study was to investigate whether trans- Percutaneous closure is a safe and effective treatment for catheter closure of interatrial septal communications the closure of an atrial septal defect (ASD) and patent for- leads to myocardial injury, by measuring the serum con- amen ovale (PFO) . The increase in cardiac troponin T centration of TnT before and after catheter closure in (TnT) is a sensitive and specific marker of myocardial adults, and to try to determine the cause of such an damage. It has been found that the increase in TnT level elevation. after elective percutaneous coronary intervention predicts future cardiac events . Limited data are available on the Methods increase in TnT after transcatheter closure of interatrial Fifty-one patients who had undergone transcatheter septal defects, and the specific mechanism of myocardial ASD and PFO closure at the University Hospital in damage is not yet fully understood [3–6]. Lund, Sweden, from 2010 to 2016, were studied retro- spectively. The characteristics of the patients are given * Correspondence: Joanna.Hlebowicz@med.lu.se in Table 1. Electrocardiograms were obtained before the Department of Cardiology, Skåne University Hospital, Lund University, SE-221 85 Lund, Sweden procedure and 1 day after the procedure. Cardiac © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hlebowicz et al. Journal of Congenital Cardiology (2018) 2:4 Page 2 of 5 Table 1 Clinical characteristics of the 51 patients before and 1 day after transcatheter closure of an atrial septal defect (ASD) or patent foramen ovale (PFO). The three patients who only underwent diagnostic balloon sizing of the defect are included in the ASD group. Differences in age, BSA, degree of TnT elevation, the procedural duration, defect size and device size between the subjects who underwent transcatheter ASD and PFO closure were evaluated with the Mann–Whitney U-test. Chi-squared analysis was used to examine the distribution of the cardiovascular risk factors and sex across the groups ASD PFO p-value Number of patients, n (%) 36 (71) 15 (29) Age, years (mean/range) 52 / 22–80 52 / 17–74 ns Female, n (%) 29 (81) 6 (40) 0.004 BSA (m ) 1.86 ± 0.21 1.97 ± 0.22 ns Cardiovascular risk factors (%) Hypertension 33 33 ns Smoking 6 7 ns Dyslipidemia 3 7 ns Impaired renal function 0 0 ns Procedural data Device size: ASD waist/PFO disc (mean ± SD, mm) 22.8 ± 5.4 24.9 ± 3.9 ns Defect size: stretched diameter (mean ± SD, mm) 22.8 ± 6.2 11.9 ± 3.2 0.000 Procedural duration (mean ± SD, min) 58.9 ± 11.5 48.1 ± 11.7 0.006 Biochemical results TnT increase ≥5 ng/, n (%) 32 (89) 15 (100) ns TnT increase (mean ± SD, ng/L) 18 ± 23 13 ± 10 ns ns not significant rhythm was monitored during the procedure and the Vascular access was obtained via the femoral vein. day after. Transthoracic echocardiography was per- Heparin (100 IU/kg) and a single dose of prophylactic formed before, and 1 day after, the procedure. Blood antibiotics (cloxacillin) were given. A sizing balloon was samples were taken for the analysis of TnT 1 day before positioned in the ASD or PFO in all cases to measure the intervention and 1 day after the intervention. All the stretched diameter of the defect. The procedure was laboratory analysis was carried out at the laboratory of guided by transesophageal echocardiography in all cases, the University Hospital in Lund, using the commercial and was used to measure the defect diameter, the pos- version of the TnT assay . The lower detection limit ition in the interatrial septum, surrounding structures, for TnT was 5 ng/L. The interassay coefficient of vari- the position of the sizing balloon, the device position ability was 2% at 16 ng/L, and 2.0% at 240 ng/L. The and stability, and to detect any residual shunt. An intraassay coefficient of variability was 0.6% at 16 ng/L Amplatzer Septal Occluder was used in 46 cases, and an and 0.6% at 100 ng/L. Occlutech Figulla septal occluder in 2 cases. Periproce- In one patient, transcatheter closure was performed dural complications were limited: two patients exhibited under general anesthesia with propofol. All other pa- transient (< 5 min) inferior ST elevation during the pro- tients were awake, receiving midazolam for sedation if cedure, and two patients suffered from atrial arrhythmia needed. Six of the patients with ASD and one of the during the procedure. patients with PFO were receiving antithrombotic treat- The study was approved by the Ethics Committee at ment with warfarin before and after the procedure. One Lund University, and performed according to the of the patients with ASD and eight of the patients with Declaration of Helsinki. PFO were receiving Novel Oral AntiCoagulants (NOAC) before and after the procedure. All of the Statistical analysis other patients (n = 35) received routinely antithrom- Results are given as mean values and SD, unless other- botic treatment with aspirin the day before the proced- wise stated. Changes in the level of TnT were calculated ure and this was maintained at a dose of 160 mg daily as the difference between the level before the interven- for at least 6 months after ASD (or PFO closure. If PFO tion (baseline) and 24 h after the intervention. The closure because of cryptogenic stroke aspirin was pre- elevation of TnT was evaluated with the Wilcoxon t- scribed lifelong, however, in a lower dose of 75 mg after test. Differences in the degree of TnT elevation, the pro- 6months. cedural time, defect size and device size between the Hlebowicz et al. Journal of Congenital Cardiology (2018) 2:4 Page 3 of 5 subjects who underwent transcatheter ASD and PFO (p = 0.004). The mean procedural duration of ASD clos- closure were evaluated with the Mann–Whitney U-test. ure was 58.9 ± 11.5 min, which was significantly longer Chi-squared analysis was used to examine the distribu- (p = 0.006) than that of PFO closure, 48.1 ± 11.7 min. The tion of cardiovascular risk factors and sex across the mean stretched diameter of the ASD was 22.8 ± 6.2 mm; groups. Possible relations between TnT elevation and significantly larger (p = 0.000) than the diameter of the age, body weight, body surface area (BSA), duration of PFO, 11.9 ± 3.2 mm. the intervention, or size of the implanted device were The mean TnT level at baseline in the ASD group analyzed with the Pearson correlation. (n = 33) was 6.8 ± 4.9 ng/L, and increased significantly, All statistical calculations were performed using SPSS to 26.4 ± 23.3 ng/L (p = 0.000), 1 day after ASD clos- for Windows (version 22.0, 2016). Values of p < 0.05 ure. The increase in TnT was significantly correlated were considered to indicate statistically significant to the stretched diameter of the ASD (r = 0.424, p =0. differences. 010), as well as to the size (waist) of the implanted ASD device (r = 0.542, p = 0.001), and the duration of Results the procedure (r = 0.348, p = 0.035) (Fig. 1). The TnT Catheter closure was performed in 48 of the 51 patients elevation after ASD closure was not correlated with (94%). In the other three patients (all ASD) only diag- the patient’s age, body weight or BSA. nostic balloon sizing of the defect was performed, and The mean TnT level at baseline in the PFO group no attempt was made to close the defect. These three (n = 15) was 7.1 ± 3.2 ng/L, and increased significantly, patients were included in the ASD group. A TnT level ≤ to 19.7 ± 12.0 ng/L (p = 0.001), 1 day after PFO clos- 5 ng/L (i.e. the lower detection limit) was found at base- ure. The TnT elevation was not correlated with the line in 37 of the 51 patients (73%), and 1 day after the balloon-stretched size of the PFO, the duration of the procedure in 5 of the patients (10%). The level of TnT intervention, the size (largest disc) of the PFO device was ≥15 ng/L at baseline in three patients (6%, one ASD nor with the patient’sage,bodyweight orBSA. closure, one ASD balloon sizing only, and one PFO clos- Three patients (all in the ASD group) underwent ure), and an increase in TnT was found in 47 patients diagnostic balloon sizing of the defect without any (92%) 1 day after the procedure (Table 1). The age, BSA, attempt to close it. However, an increase in TnT was TnT elevation and cardiovascular risk factors did not observed in one of these patients 1 day after the pro- differ between the ASD and the PFO groups (Table 1). cedure (TnT 2 ng/L, 1 ng/L, and 49 ng/L, There were significantly more women in the ASD group respectively). Fig. 1 Correlations between TnT elevation and (a) the size (waist) of the implanted ASD device, (b) the stretched size of the ASD, and (c) the duration of the procedure, evaluated with the Pearson correlation. Each data point represents an individual patient Hlebowicz et al. Journal of Congenital Cardiology (2018) 2:4 Page 4 of 5 The mean TnT level at baseline in the group receiving cardiac output by the balloon, causing ventricular strain warfarin or NOAC (n = 16) was 9.0 ± 6.9 ng/L, and in- and myocardial injury . Cardiac catheterization alone creased significantly, to 29.8 ± 31.9 ng/L (p = 0.001) 1 day has been reported not to lead to an increase in TnI in chil- after PFO or ASD closure. The mean TnT level at baseline dren , however, it is unclear whether balloon sizing was in the group receiving aspirin (n = 35) was 5.1 ± 2.5 ng/L, performed in that study. and increased significantly, to 22.3 ± 12.7 ng/L (p =0.000), An increase in TnT was also seen after PFO closure, 1 day after PFO or ASD closure. The TnT elevation was but this was not correlated with the balloon-stretched not significantly different between the group receiving size of the PFO or the size of the PFO device. However, warfarin and NOAC or aspirin (p =0.474). PFO devices have a very narrow waist, and the desig- nated size of PFO devices reflects the size of the largest Discussion disc; thus the strain on the rim/edge of the defect would The aim of this study was to determine whether catheter be lower. Nevertheless, TnT was elevated after PFO closure of an atrial septal defect leads to myocardial in- closure, suggesting that the discs of the device may con- jury, and to determine the cause. Our finding, that cath- tribute to the release of TnT. However, a slight increase eter closure of an ASD or PFO causes a minor in TnT level can be caused by balloon sizing alone. myocardial injury, is in accordance with earlier studies The increase in TnT in the ASD and PFO groups was using troponin I (TnI) as a marker of myocardial dam- not statistically significantly different, although a some- age [3–6]. The number of patients in these studies was what greater increase in TnT was seen after the ASD about the same as in the present study. We also found intervention. The duration of the ASD procedure is sig- that in patients with ASD, the extent of myocardial dam- nificantly longer than in PFO closure, and TnT elevation age, expressed as the increase in TnT, was related to the was related to the procedural time in the ASD group. waist size of the implanted ASD device. As the choice of This finding is in contrast to the study mentioned above, device is based on balloon sizing, the size of the device on ASD closure in children and adults, where no such is related to the stretched ASD diameter. It has also relation was found . PFO closure is usually straight- been found in previous studies on both children and forward, while the closure of ASDs, particularly large adults that the elevation of TnI was related to the size of ones, may require more or longer manipulation. If so, the implanted device [3, 6]. The larger the device, the the larger device size and repeated minor trauma caused greater the number of myocytes affected by mechanical by the catheter may explain our findings. stress, and it is thus logical to assume that a larger de- When the patient is in the supine position, air bubbles vice will lead to a greater increase in TnT. In one of the from the long sheaths may reach the right coronary studies mentioned above it was suggested that the artery due to the anterior position of the right sinus of increase in TnI was caused by transient, reversible myo- Valsalva, and coronary air embolism has been reported cardial membrane instability caused by the device, how- in the systemic circulation during ASD catheter closure ever, the relation to device size was not analyzed in that [9, 10]. In the present study, transient inferior ST eleva- study . In a study on children, the ratio of the device tion occurred in two patients during the ASD procedure size to BSA was reported to be correlated to the magni- and an increase in TnT level was observed. The one tude of the myocardial injury . This was not the case with the highest TnT increase observed in this study in our study. One reason for this may be that the vari- was 121 ng/L. This increase could be explained by cor- ation in BSA in adults is much lower than in children, onary air embolism and a minor ventricular injury. If the making correlations more difficult to identify. patients had level of TnT was ≥15 ng/L the TnT was We found an increase in TnT in one of the three controlled to return to baseline. Unfortunately, lower patients undergoing balloon sizing only, in contrast to a levels TnT between 5 and 15 ng/L were not followed up. previous study on diagnostic balloon sizing in seven Therefore we cannot exclude leakage of low TnT elevels patients, where no significant elevation of TnI was seen for a longer time. Transthoracic echocardiography was . However, the small number of patients undergoing performed 1 day after closure, and no changes were this procedure in the present study makes statistical ana- observed in the left ventricular ejection fraction or wall lysis of this group impossible. Nevertheless, is appears motion, thus significant myocardial injury appears that stretching the interatrial septum may cause mild unlikely. myocardial injury. An increase in TnI has also been re- In our study 16 patients with ASD or PFO were re- ported after other transcatheter interventions such as ceiving antithrombotic treatment with warfarin or balloon dilation and the insertion of a stent in the pul- NOAC before and after the procedure. All of the other monary artery in one child aged 1.6 years and in the de- patients received treatment with aspirin the day before scending aorta in another aged 13.4 years . However, in the procedure and after the ASD or PFO closure. In our these cases this was explained by the acute obstruction of study the TnT elevation was not significantly different Hlebowicz et al. Journal of Congenital Cardiology (2018) 2:4 Page 5 of 5 between the group receiving warfarin and NOAC or as- Ethics approval and consent to participate The study was approved by the Ethics Committee at Lund University, pirin. After transcatheter closure of an ASD defect a Sweden, Dnr 2016/525. mild increased coagulation activation has been observed with increased prothrombin fragments after device im- Competing interests The authors declare that they have no competing interests. plantation up to 3 months after the device implantation [11, 12]. However, no platelet activation was observed Publisher’sNote [11, 12]. Therefore the question has been raised whether Springer Nature remains neutral with regard to jurisdictional claims in we should use anticoagulant instead of antiplatelet ther- published maps and institutional affiliations. apy after closure of ASD defects. In our study the nitinol Received: 12 January 2018 Accepted: 27 April 2018 wire devices might have activated the coagulation in a short period causing microvascular myocardial injury. Unfortunately the troponin levels were only measured 1 References 1. Kefer J, Sluysmans T, Hermans C, et al. Percutaneous transcatheter closure of day before the intervention and 1 day after the interven- interatrial septal defect in adults: procedural outcome and long-term results. tion. Therefore can a longer leak of troponin not be Catheter Cardiovasc Interv. 2012;79(2):322–30. excluded. The coagulation returns to normal levels after 2. Ricciardi MJ, Davidson CJ, Gubernikoff G, et al. Troponin I elevation and cardiac events after percutaneous coronary intervention. Am Heart J. 2003; 1–3 months [11, 12] and this has been explained caused 145(3):522–8. by endothelialization of the ASD devices within 1– 3. Tárnok A, Bocsi J, Osmancik P, Häusler HJ, Schneider P, Dähnert I. 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Experience The most important finding of this study is that patients with transcatheter closure of secundum atrial septal defects using the Amplatzer septal occluder: a single Centre study in 236 consecutive undergoing uncomplicated catheter closure of an ASD or patients. Heart. 2003;89(2):199–204. PFO experience minor and clinically insignificant myocar- 11. Rodés-Cabau J, Palacios A, Palacio C, et al. Assessment of the markers of dial injury as evidenced by the levels of TnT following the platelet and coagulation activation following transcatheter closure of atrial septal defects. Int J Cardiol. 2005;98(1):107–12. procedures. From the point of differential diagnoses, this 12. Zeng XC, Wu WF, Huang K, Guo SL, Liu TW. Enhanced prothrombin knowledge is important when dealing with complications formation and platelet activation in Chinese patients after transcatheter after ASD and PFO catheter closure. The mechanical closure of atrial septal defect. Clin Cardiol. 2010;33(7):E6–9. 13. Lock JE, Rome JJ, Davis R, et al. Transcatheter closure of atrial septal defects. trauma caused by insertion of the device appears to be the Experimental studies. Circulation. 1989;79(5):1091–9. main mechanism responsible for this increase, as the cir- 14. Sharafuddin MJ, Gu X, Titus JL, Urness M, Cervera-Ceballos JJ, Amplatz K. cumference of the waist of the device is directly related to Transvenous closure of secundum atrial septal defects: preliminary results with a new self-expanding nitinol prosthesis in a swine model. Circulation. the affected area of the myocardium. The ASD devices 1997;95(8):2162–8. seem to have a greater effect than PFO devices probably due to their larger waist. Abbreviations ASD: Atrial septal defect; PFO: Patent foramen ovale; TnT: Troponin T Availability of data and materials The datasets generated during the current study are not publicly available but are available from the corresponding author on reasonable request. Authors’ contributions The authors’ contributions were as follows: JH and UT contributed to the design of the study; JH performed the statistical calculations and wrote the first draft of the manuscript. JH, UT, JH and NI critically revised the manuscript. All authors have read and approved the final manuscript.
Journal of Congenital Cardiology
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Published: Jun 5, 2018