Atrial and Brain Natriuretic Peptide Secretion After Percutaneous Closure of the Left Atrial Appendage With the Watchman Device

Abstract: Objective. To evaluate the effect of transcatheter closure of the left atrial appendage (LAA) with the Watchman device on the secretion of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Background. The LAA plays an important role in the regulation of intravascular volume via release of ANP and BNP. To date, there are no data suggesting substantial effects of hormonal interaction after percutaneous LAA closure for prevention of thromboembolic events in patients with non-valvular atrial fibrillation. Methods. From October 2009 until May 2010, transcatheter LAA closure using the Watchman device was performed in 31 patients with non-valvular atrial fibrillation. Venous blood samples were obtained before, immediately after device implantation, and prior to discharge for ANP and BNP measurements. Results. LAA closure resulted in a significant increase in ANP and BNP levels immediately after the procedure compared with baseline measurements (ANP: from 241 ± 34 pg/mL to 329 ± 30 pg/mL, P<.05; BNP: from 579 ± 196 pg/mL to 698 ± 211 pg/mL, P<.05), and a significant decrease prior to discharge compared with baseline values (ANP: from 241 ± 34 pg/mL to 149 ± 30 pg/mL, P<.001; BNP: from 579 ± 196 pg/mL to 429 ± 147 pg/mL, P<.001). Conclusions. These results suggest that percutaneous closure of the LAA results in an intermittent distribution of the vasoactive hormones ANP and BNP followed by a significant attenuation of ANP and BNP secretion in the early postprocedural period. The clinical impacts of these findings need to be evaluated in further studies.

J INVASIVE CARDIOL 2015;27(10):448-452. Epub 2015 May 15

Key words: atrial fibrillation, LAA closure

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The left atrial appendage (LAA) is the most common source of cardiac thrombus formation in patients with non-valvular atrial fibrillation. More than 90% of all thrombi in patients with non-rheumatic atrial fibrillation forming in the left atrium originate in the LAA.¹ Percutaneous occlusion systems have been developed as an alternative to anticoagulation for stroke prevention. Four different devices have been designed specifically for occlusion of the LAA: the Percutaneous LAA Transcatheter Occlusion system (PLAATO; ev3), the Watchman LAA system (Boston Scientific), the Amplatzer Cardiac Plug (AGA Medical), and the WaveCrest LAA Occluder (Coherex Medical). Although safety and feasibility of the PLAATO device have been proven in several non-randomized studies, the device has been withdrawn from the market due to commercial reasons.^2-4 Initial experiences with the Amplatzer Cardiac Plug and the Coherex WaveCrest have been recently published.^5,6 To date, only the Watchman device has demonstrated non-inferiority versus standard treatment with chronic warfarin administration in a prospective randomized, controlled trial.⁷

Each system has unique features, but the implantation method is the same, ie, transseptal vein puncture is performed to gain access to the LAA. Thereafter, the device is inserted into the orifice of the LAA under fluoroscopic and echocardiographic guidance.

Under physiologic circumstances, the LAA is contractile and plays a central role in regulation of intravascular volume via release of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Both ANP and BNP are produced within the heart and are released into the circulation in response to increased myocyte stretch due to volume and pressure overload. It has been shown that natriuretic peptides are mainly secreted by way of coronary sinus into the general circulation.⁸

 These peptides regulate blood pressure and volume by diuretic, natriuretic, and vasodilatation actions, as well as inhibition of the sympathetic nervous system and the renin-angiotensin-aldosterone axis. In addition, ANP and BNP play a role in cardioprotection by regulating cellular growth, cellular proliferation, and cardiac hypertrophy.^9,10

ANP is produced, stored, and released in both atria and particularly in both atrial appendages.¹¹ It has been shown that plasma ANP levels depend on LAA wall stress, rather than LA wall stretch or pressure.¹² Besides the left ventricle, BNP is also produced and released from the left atrium and especially the LAA in patients with atrial fibrillation.¹³

In several animal studies, right or bilateral atrial appendectomy led to reduced ANP release.^14-18 In addition, Yoshihare et al¹⁹ demonstrated attenuated ANP secretion after maze procedure in the early postoperative period, as well as in the chronic phase.

To date, there are no data suggesting substantial effects of hormonal interaction after percutaneous LAA closure. Our hypothesis was that by excluding the LAA from circulation, the physiologic stimuli for ANP and BNP synthesis and release may be impaired. The aim of our study was therefore to evaluate the amount of circulating ANP and BNP immediately after LAA closure and in the early postprocedural period.

Methods

Between October 2009 and May 2010, thirty-one consecutive patients with non-valvular atrial fibrillation and a minimum CHADS₂ score of 2 underwent transcatheter closure of the LAA in our institution. Due to contraindications to oral anticoagulation, 14/31 patients (45%) were not candidates for anticoagulation therapy, 12/31 patients (39%) refused to take oral anticoagulation, and 5/31 patients (16%) had a labile international normalized ratio and a novel oral anticoagulant was not an alternative due to an advanced chronic renal insufficiency. Routine examination before the procedure included electrocardiography, standard blood tests, and transthoracic (TTE) and transesophageal echocardiography (TEE).

The Watchman LAA closure device. The Watchman LAA closure device consists of a nitinol frame that has 10 barbs for anchoring the device within the LAA myocardium. The device is covered on the luminal side with a polyethylterephtalate fabric cap that has 160 micron pores to prevent thrombus dislocation from the LAA immediately after implantation and allow device endothelialization. Several animal models have shown that device endothelialization is complete 45 days after implantation.

Details regarding transcatheter device implantation were similar to those reported previously.^2-5,7 Briefly, transseptal puncture was performed to gain access to the LAA under echocardiographic control. After entering the left atrium, left atrial pressure was measured. To avoid undersizing of the LAA, 0.9% sodium chloride solution was administered to achieve a mean filling pressure of the left atrium in the high-normal range (>10 mm Hg). Thereafter, LAA angiography was performed. Iopromide (Ultravist; Bayer HealthCare), a non-ionic, water-soluble x-ray contrast agent was used for LAA angiography.

 After optimal device size selection based on LAA measurements by fluoroscopy and echocardiography, the device was implanted into the orifice of the LAA under fluoroscopic and TEE control. To prevent device embolization and to have optimal device stability independent of cardiac decompensation or change in the underlying rhythm, the size of the device was chosen to be 10%-20% larger than the maximum diameter of the LAA ostium to achieve a compression of the device of at least 8%.Every procedure was performed under both local anesthesia and conscious sedation for TEE control. Heparin was given during the implantation procedure to achieve an activated clotting time of at least 250 seconds.

The day after the procedure, TTE and chest x-ray were performed in all patients. After confirming the correct position of the device and exclusion of complications, the patients were discharged. All patients were discharged on life-long aspirin 100 mg/day. Additionally, in patients who could tolerate oral anticoagulation (n = 17; 55%), warfarin was started the day after the procedure for at least 45 days (target international normalized ratio between 2.0 and 3.0). In the remaining patients with contraindications to warfarin (n = 14; 45%), clopidogrel 75 mg/day was prescribed for 6 months after the procedure in addition to aspirin.

All of the procedures were adequately explained to the patients, and informed consent was obtained. The study was approved by the Ethics committee of the University Leipzig (clinical trial NCT01522911).

Blood sampling. Venous blood samples were taken before the procedure, immediately after implantation of the LAA closure device, and on the first day after the procedure from a peripheral vein. The blood was drawn into plastic tubes containing aprotinin and ethylenediaminetetraacetic acid disodium and was promptly centrifuged. The plasma obtained was stored at -20 °C until assayed. The plasma BNP and ANP concentrations were determined with commercially available enzyme immunoassay kits (ELISA for BNP, Uscn Life Science, Inc; ELISA for ANP, HölzelDiagnostika).

Statistical analyses. Data are presented as mean ± standard error of the mean. All statistical analyses were performed with the use of SAS statistical software, version 9.1 (SAS Institute). A repeated measures analysis of variance (ANOVA) was used to compare the ANP and BNP measurements at different time points. Differences were considered statistically significant when a P-value <.05 was obtained.

Results

Baseline characteristics. Patient characteristics at baseline are summarized in Table 1. Preprocedural TEE evaluation of the LAA showed an ostium width of 20 ± 4 mm (range, 16-32 mm) and length of 34 ± 7 mm (range, 21-46 mm). Most of the patients had permanent or persistent atrial fibrillation (n = 20; 65%).

Periprocedural results. Device implantation was successful in all 31 patients. Two-thirds of the patients had atrial fibrillation during implantation (n = 20; 65%). Mean non-invasive blood pressure was 138/78 mm Hg before the procedure and 145/82 mm Hg after the procedure. Mean left atrial pressure after transseptal puncture was 10 ± 3 mm Hg. Mean amount of contrast dye used for angiography of the LAA was 118 ± 32 mL. The Watchman occluder was used in all patients. The selected device size ranged from 21-33 mm. In detail, a 33 mm device was implanted in 1 patient (3%), a 30 mm device in 4 patients (13%), a 27 mm device in 6 patients (19%), a 24 mm device in 11 patients (35%), and a 21 mm device in 8 patients (26%). In 3 patients (10%), the initially chosen device had to be exchanged during the procedure. A larger device was implanted in 2 patients and a smaller device was implanted in 1 patient. After implantation of the device, mean compression was 15 ± 3%. There was no correlation between the degree of device compression and the change in ANP and BNP values after implantation. Mean fluoroscopy time was 8 ± 3 minutes. In 1 patient (3%), an air embolism to the right coronary artery occurred immediately after successful device implantation. Catecholamine and intubation were necessary due to hemodynamic instability. Restoration of normal coronary flow was achieved after aspiration of the air. The patient was monitored in the intensive care unit for several hours and discharged without sequelae 48 hours later. This patient has been excluded from the statistical analysis.

In all patients, a pericardial effusion was excluded the day after device implantation. No additional peri- or postprocedural complications occurred in our patient cohort. The mean hospital stay after the procedure was 28 ± 3 hours.

Plasma ANP and BNP levels. Compared with baseline values, LAA closure resulted in a significant increase in ANP and BNP levels immediately after the procedure (ANP: from 241 ± 34 pg/mL to 329 ± 30 pg/mL, P<.05; BNP: from 579 ± 196 pg/mL to 698 ± 211 pg/mL, P<.05) and a significant decrease prior to discharge (ANP: from 241 ± 34 pg/mL to 149 ± 30 pg/mL, P<.001; BNP: from 579 ± 196 pg/mL to 429 ± 147 pg/mL, P<.001) (Figures 1 and 2).

Discussion

Percutaneous closure of LAA has been developed as an alternative to oral anticoagulation for primary and secondary prevention of thromboembolic events in patients with non-valvular atrial fibrillation. The basic objective of this technique is to exclude the LAA completely from circulation to prevent thrombus dislocation from the LAA. As described above, the important role of the LAA in pressure sensing and cardiorenal homeostasis by the release of ANP and BNP is well established.^10,20

Atrial fibrillation per se is associated with increased plasma concentrations of natriuretic peptides regardless of heart failure reflecting atrial dysfunction.^13,21 Sacher et al²² reported the change of circulating natriuretic peptide levels in patients with atrial fibrillation after pulmonary vein isolation. In this study, ANP and BNP plasma concentrations were measured before, 1 day, 3 days, and 3 months after successful pulmonary vein isolation. They observed a significant decrease on day 1, and an increase at day 3 and at the end of the month 3, without reaching the values before pulmonary vein isolation. In contrast to our study, natriuretic peptide levels were not measured immediately after ablation therapy.

In a study by Chamakou et al,²³ ANP and BNP concentrations were measured in 28 patients before and 1 month, 3 months, and 6 months after transcatheter closure of an atrial septal defect. Thirty-three healthy volunteers were studied as controls. ANP concentrations increased during the first month and remained high 6 months after the procedure. BNP concentrations increased during the first month, but decreased to normal values 3 months after the procedure. In contrast to our study, natriuretic peptide levels were not measured immediately after the procedure. 

Several studies have demonstrated that right atrial or bilateral atrial appendectomy in animal models suppressed a volume-dependent rise in ANP and significantly reduced the early diuresis and natriuresis to acute large-volume expansion.^14-18 In a study by Yoshihara et al,¹⁹ the maze procedure (which includes bilateral atrial appendectomy) reduced ANP secretion in the early postoperative period and persisted in the chronic phase. The authors concluded that this attenuated atrial natriuretic peptide secretion may reduce the ability of the kidneys to handle fluid load early after surgery.

It is reasonable that removing the main production site of ANP will lead to a decrease of ANP secretion. As mentioned above, natriuretic peptides are not released directly into the cavity of the LAA, but rather into the coronary sinus, and closure of the LAA will not remove the main production and releasing site of natriuretic peptides. Nevertheless, it is conceivable that LAA closure and consecutive exclusion of blood flow may result in an inhibition of LAA wall stretch, the most important factor affecting natriuretic peptide secretion. In this prospective observational study, we investigated whether transcatheter LAA closure with the Watchman system affected ANP and BNP secretion.

In our study, percutaneous LAA closure was performed successfully in all 31 patients. We had 1 periprocedural complication without sequel. No complications occurred after the procedure or through discharge. Venous blood samples were taken directly before transseptal puncture, after device implantation, and 24 hours after device implantation.

Immediately after percutaneous LAA closure, ANP and BNP values increased significantly compared with baseline measurements, which is most likely due to injection of contrast dye into the LAA and stretching of the LAA by the closure device. Twenty-four hours after the procedure, ANP and BNP values decreased significantly compared with baseline values. We did not perform a control TEE the day after the procedure, but the suggestion of these results is that device implantation and consecutive LAA flow limitation in the early phase might lead to the observed reduction in circulating ANP and BNP levels. In this study, the influence of percutaneous LAA closure on secretion of natriuretic peptides has been analyzed only in the early postprocedural phase. The impact of this procedure on the amount of circulating ANP and BNP during mid-term and long-term follow-up remains unclear. On one hand, it is possible that ANP and BNP values will further decrease over time due to advanced endothelialization of the device surface and consecutive progress in complete closure of the LAA. On the other hand, the loss of ANP and BNP secretion via the LAA may be compensated by an increased production in other myocytes, for example in the right atrial appendage. In addition, the potential clinical impact of these findings was not evaluated in this study. Therefore, further studies are necessary to reassess these findings during a longer follow-up period and to evaluate potential clinical effects.

Study limitations. There are several limitations to this study. The number of patients is rather limited and there is no long-term follow up available. Usually, the occluder device size is chosen to be larger than the maximal diameter of the LAA ostium to ensure proper compression and subsequently a stable device position. This may influence the myocyte stretch and subsequent ANP and BNP secretion. In addition, the potential residual flow through the device may also influence ANP and BNP values. 

As mentioned above, plasma concentrations of natriuretic peptides also transiently increased after percutaneous closure of atrial septal defects and pulmonary vein isolation. Therefore, it may also be postulated that the manipulations in the left atrium and not the closure of either the atrial septal defect or the LAA caused the changes in plasma natriuretic peptide concentrations. Furthermore, procedural stress, sedation, contrast dye, and the amount of intravenous fluid given during the procedure might affect the results.

Conclusion

These results suggest that percutaneous closure of the LAA with the Watchman device significantly increases the release of natriuretic peptides during device implantation and attenuates the release of ANP and BNP in the very early postprocedural period.

These findings indicate a loss of neurohumoral function of the LAA in the short-term follow-up period 24 hours after device implantation. The persistence of these findings during mid-term and long-term follow-up, as well as clinical impacts, need to be evaluated in further studies.

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From the ¹University of Leipzig, Heart Center, Department of Internal Medicine/Cardiology, Leipzig, Germany; ²University of Leipzig, Heart Center, Department of Pediatric Cardiology, Leipzig, Germany; and ³Asklepios Clinic Weissenfels, Department of Cardiology, Weissenfels, Germany.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Moebius-Winkler, Dr Daehnert, and Dr Schuler participated in the Protect AF trial. Dr Moebius-Winkler and Dr Daehnert report consulting speaker honoraria from Boston Scientific. Dr Moebius-Winkler and Dr Sandri work as proctors for Watchman implantation for Boston Scientific.

Manuscript submitted November 10, 2014, provisional acceptance given November 24, 2014, final version accepted February 2, 2015.

Address for correspondence: Nicolas Majunke, MD, University of Leipzig, Heart Center, Department of Internal Medicine/Cardiology, Strümpellstrasse 39, 04389 Leipzig, Germany. Email: Nicolas.majunke@medizin.uni-leipzig.de