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Comparative Pathology of an Implantable Left Atrial Pressure Sensor

Trainor, Karen E.*; Roberts, Aaron*; Weeks, Brad*; Jackson, Nicolette*; Troughton, Richard W.†‡; Charles, Christopher J.; Rademaker, Miriam T.; Melton, Iain C.†‡; Crozier, Ian G.†‡; Hafelfinger, Werner§; Gutfinger, Dan E.§; Eigler, Neal L.§; Abraham, William T.; Clubb, Fred J. JR*

doi: 10.1097/MAT.0b013e31829bdffd
Clinical Cardiovascular/Cardiopulmonary Bypass

A left atrial pressure (LAP) monitoring system was developed for guiding the management of patients with heart failure. The LAP sensor is implanted into the left atrium via transseptal catheterization and affixed to the interatrial septum by nitinol anchors. The long-term safety of permanent implantation of the LAP sensor in patients was evaluated based on the comparative pathology in animals. Tissue specimens of the LAP sensor from 7 patients, 49 canines, and 14 ovine were examined for thrombosis and tissue overgrowth. Implant duration ranged from 22 to 1,686 days. Gross examination showed minimal-to-moderate tissue overgrowth with no evidence of migration, erosion, or perforation. There was no excessive host-to-device reaction or active thrombogenesis in any of the subjects that followed the antithrombotic therapy protocol. Micro-computed tomography scanning confirmed the structural integrity of the device. Low vacuum scanning electron microscopy and histology showed neoendocardial tissue overgrowth with no inflammation or fibrin. The pathology of both animal models was found to closely approximate the pathology in humans and favorably supports the long-term safety of the device.

From the *Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas; Department of Cardiology, Christchurch Hospital, Christchurch, New Zealand; and Christchurch Heart Institute, University of Otago, Christchurch, New Zealand; §St. Jude Medical, Implantable Electronic Systems Division, Sylmar, California; and Ohio State University Division of Cardiovascular Medicine, Columbus, Ohio.

Submitted for consideration February 2013; accepted for publication in revised form May 2013.

Disclosures: The study was sponsored by St. Jude Medical, Sylmar, California. Drs. Gutfinger and Eigler and Mr. Hafelfinger are employed by St. Jude Medical and disclose a financial interest in the manufacturer of the study device. Drs. Trainor, Clubb, Troughton, Melton, Crozier, and Abraham report receiving honoraria or consulting fees from St Jude Medical or other companies that manufacture devices. The other authors report no conflicts.

Reprint Requests: Dr. Fred J. Clubb, Cardiovascular Pathology Laboratory, Texas A&M University, 4467 TAMU, College Station, TX 77843. Email: FClubb@cvm.tamu.edu.

Implantable hemodynamic monitoring systems for guiding the management of patients with heart failure have been investigated with the aim of reducing hospitalizations for acute decompensated heart failure.1–3 One such system is an implantable left atrial pressure (LAP) monitor linked to a physician-directed patient self-management treatment paradigm.2 Early clinical experience with the LAP monitoring system demonstrated improved LAP control, reduced heart failure symptoms, more optimal neurohormonal antagonist and diuretic dosing, and a reduction in early clinical events.2 Left atrial pressure monitoring may also be useful for optimizing the filling pressure in left ventricular assist device patients or for guiding the decision for cardiac transplantation.

Although early studies showed that the LAP monitoring system can be implanted safely, a close evaluation of the histopathological appearance of the implanted sensor is critical for demonstrating long-term safety. Evaluation of the histopathology is also important because coverage of the sensor with tissue has the potential to affect the LAP measurements and the ability to safely extract the device.3,4 A description of the histopathology of the LAP sensor based on a comparative pathology evaluation is presented in this article.

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Methods

The implanted portion of the LAP monitoring system (HeartPOD™; St. Jude Medical, Sylmar, CA) consists of a transvenous implantable sensor lead that is connected at its proximal end to a subcutaneous antenna coil. The antenna coil is available either as a stand-alone module or in combination with a cardiac resynchronization therapy defibrillator generator. The sensor module (Figure 1) at the distal end of the implantable sensor lead is implanted into the left atrium via transseptal catheterization and affixed to the interatrial septum by folding nitinol anchors.3

The fixation anchors were originally positioned along the sensor module so that the sensor diaphragm would minimally protrude (<1 mm) into the left atrium (anchor location “A”). However, LAP waveform artifacts secondary to excessive tissue overgrowth were seen in 20% of initial implants.3 To eliminate LAP waveform artifacts, the location of the fixation anchors was moved so that the sensor diaphragm would protrude an additional 1.5 mm into the left atrium (anchor location “B”), and implanting physicians were trained to avoid placing devices via patent foremen ovale (PFO) tunnels and to achieve a more orthogonal placement of the device.

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Human Specimens

All human specimens were obtained at the time of autopsy from patients who participated in the Hemodynamically Guided Home Self-Therapy in Severe Heart Failure Patients (HOMEOSTASIS) trial.2 The HOMEOSTASIS trial was approved by the US Food and Drug Administration (IDE G050018), and the appropriate institutional and ethics committee approval was obtained at each center. All subjects gave written informed consent to participate in the trial. For patients from whom histopathology specimens were available, permission to perform an autopsy with device explant was also obtained.

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Animal Specimens

Because of the limited number of human specimens, additional specimens from animals were used. The animal study protocols were approved by the Animal Ethics Committee of the University of Otago, Christchurch, New Zealand, and the animal care and use committees of St. Jude Medical and Cedars-Sinai Medical Center, Los Angeles, CA. Implants were performed in an ovine and canine model, as previously described.5,6

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Antithrombotic Protocol

To minimize the risk of thromboembolic complications, patients were administered with aspirin (150–325 mg) orally 2 to 24 hours before implant. In addition, intravenous heparin was administered to patients after transseptal catheterization to achieve an activated clotting time between 200 and 300 seconds during device deployment and anchoring. After implant, a dual-agent antiplatelet therapy consisting of aspirin (50–325 mg/d) and clopidogrel (75 mg/d) was required in patients for a minimum of 6 months. In patients requiring chronic anticoagulation for other indications, such as atrial fibrillation, only single-agent antiplatelet therapy was additionally required postimplant. Beyond 6 months of implant, patients were encouraged to remain on a minimum of a single antiplatelet agent indefinitely.

In comparison, animals received intravenous heparin at ~100 U/kg after transseptal catheterization during the implant procedure. After implant, canines received dual antiplatelet therapy consisting of aspirin (81 mg) and clopidogrel (37.5–75 mg) for 3 months, whereas ovine received no antiplatelet or anticoagulation therapy. Beyond 3 months postimplant, none of the animals received any antithrombotic therapy. Before euthanasia, animals were administered with intravenous heparin to prevent postmortem clot formation.

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Tissue Preparation and Processing

At the time of autopsy, all subjects underwent a gross in situ examination of the LAP sensor and heart to evaluate the presence of any anomalies or thrombus within the left atrium or over the device. The lungs, kidneys, brain, spleen, and liver were examined in a subset of the canines (n = 16) for the evidence of thromboembolic events. The LAP sensor at the implant site and a several centimeter radius of adjacent tissue were excised and placed within 10% buffered formalin. A subset of the excised specimens (n = 33) subsequently underwent further analysis using integrated microscopy techniques.7

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Integrated Microscopy Techniques

Integrated microscopy techniques consisting of micro-computed tomography (micro-CT), low vacuum scanning electron microscopy (LVSEM), and light microscopy were used to maximize the usage of each specimen.

Micro-CT scanning was performed using a micro-CT system (HAWK-160XI; Nikon Metrology Inc., Brighton, MI) with the goal of looking for structural anomalies of the LAP sensor and for orientating the specimen during plastic embedding and sectioning.

Specimens that were submitted for LVSEM were processed in toto in graded ethyl alcohols, air-dried, and evaluated using a scanning electron microscope (JSM-6460LV; JEOL, Akishima, Tokyo). After scanning, the specimens were rehydrated and postfixed in formalin.

The LAP sensor with the surrounding tissue was then embedded in isobornyl methacrylate (Technovit 7200; Heraeus Kulzer, Wehrheim, Germany), and sectioned in slices of 0.8 mm longitudinally with a diamond-studded wire saw. The sections were glued to slides, ground using an automated grinder (Exakt Technologies Inc., Oklahoma City, OK), and polished. The slides were stained with hematoxylin and eosin or Molybdenum Blue (Electron Microscopy Sciences, Hartfield, PA) and examined using light microscopy. Microscopic evaluation was directed toward determining the extent of tissue coverage, cell type covering the sensor, degree of inflammation (host-to-device reaction), and the presence of any thrombus.

The tissue capsule thickness covering the sensor was measured from digital scans of the histology using Imagescope software (Aperio, Vista, CA). To determine the average thickness of tissue covering the diaphragm, the area of tissue covering was traced and then divided by the length of the sensor diaphragm that was covered with tissue in the plane of section close to midline. Only tissue that had morphologic features of neoendocardial growth was included in these tracings; well-organized, dense, native endocardium was excluded from the area measured.

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Statistics

Data are presented as a mean ± SD. Statistical comparisons for continuous variables were performed by t-test and for categorical variables by χ2 test. A 2-tailed p < 0.05 was taken to indicate the statistical significance.

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Results

Seventy-one specimens containing the LAP sensor with an implant duration ranging from 20 days to >4.5 years were evaluated (Tables 1 and 2). There were 31 specimens with the original anchor location A device and 40 specimens with the updated anchor location B device.

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Gross Pathology

The gross appearance of the tissues surrounding the sensor was similar in humans and animals (Figure 2), and the LAP sensor was found to be anchored to the interatrial septum in all subjects, with no evidence of migration, erosion, or perforation. There was minimal-to-moderate shiny glistening neoendocardial tissue covering the device, with no excessive host-to-device reaction and no evidence of active thrombogenesis in any of the subjects that followed the antithrombotic therapy protocol. There was one specimen that had an early developing thrombus (2 mm × 1 mm) adherent to one of the distal anchors from a patient (patient 6) with chronic atrial fibrillation who stopped taking the required antithrombotic therapy during his last 3 weeks of life while in hospice. There was no evidence of any thromboembolic events in the 16 canines for which additional organs were evaluated.

Neoendocardial tissue formation over the sensor diaphragm was observed in 20 of the 31 specimens (65%) with the anchor location A devices compared with only 3 of the 40 specimens (8%, p < 0.001) with the anchor location B devices (Table 3). There were a total of seven specimens (23%) with anchor location A devices that had LAP waveform artifacts, whereas none of the specimens with anchor location B devices had LAP waveform artifacts (p < 0.01).

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Micro-CT

Micro-CT imaging of the specimens confirmed the structural integrity of the implanted device and the absence of anchor fractures. Figure 3 shows three-dimensional reconstructions derived from the micro-CT scans of the explanted devices from patients 5 and 6. Patient 5 was implanted with an anchor location A device (Figure 3A), whereas patient 6 was implanted with an anchor location B device (Figure 3B). A comparison between these two devices demonstrates the additional 1.5 mm protrusion of the sensing diaphragm associated with the anchor location B device.

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Low Vacuum SEM

The LVSEM appearance of the device and surrounding tissues in humans and animals was similar and showed that the tissue covering the device is composed of well-differentiated intact endothelium with no inflammation or fibrin. Figure 4A from patient 5 demonstrates complete encapsulation of the sensor diaphragm and the distal anchors with neoendocardial tissue. This is in contrast to Figure 4B from patient 6 that demonstrates neoendocardial tissue coverage over two of the distal anchors and no coverage over the sensing diaphragm. Figure 4C from a canine implanted with an anchor location B device demonstrates complete coverage of the sensor diaphragm with neoendocardial tissue.

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Histology

Histology had a similar appearance in humans and animals and confirmed that the tissue covering the device was composed of a neoendocardium lined with a neoendothelium. Figure 5 shows the subgross histology corresponding to the LVSEM from Figure 4. The histology demonstrates that the distal fixation anchors had a similar amount of tissue coverage for both anchor location A and B devices. However, when tissue was covering the sensing diaphragm, the tissue thickness for the anchor location B devices (62 ± 9 μm, n = 3) was significantly less than that for the anchor location A devices (432 ± 240 μm, n = 13, p < 0.001).

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Left Atrial Pressure Waveform Artifacts

To evaluate the relationship between histology and LAP waveform artifacts, the available specimens were classified into three groups based on the gross and microscopic appearance. Group 1 is the largest group and is characterized by specimens that on gross and microscopic examination had no tissue coverage over the sensing diaphragm (Figures 2B and 5B). This group consisted of 11 anchor location A devices and 37 anchor location B devices. None of the devices within this group developed LAP waveform artifacts.

Group 2 is characterized by specimens that on gross examination had tissue coverage over the sensor diaphragm with one of the two additional conditions: 1) tissue thickness ≤300 μm on microscopic examination (Figure 5C), or 2) a translucent appearance when histology was not available (Figure 2A). This group consisted of 11 anchor location A devices and 3 anchor location B devices. The average tissue thickness over the sensor diaphragm for the specimens in this group that had histology (n = 7) was 144 ± 105 μm. Similar to group 1, none of the devices in the second group developed LAP waveform artifacts.

Group 3 is characterized by specimens that on microscopic examination had tissue coverage over the sensor diaphragm with a thickness >300 μm (Figures 5A). This group consisted of nine anchor location A devices. Coupling between the tissues covering the sensor diaphragm and the adjacent atrial wall was seen in six of the specimens (67%) within this group. The average tissue thickness over the sensor diaphragm for group 3 was 540 ± 207 μm (n = 9). This tissue thickness was significantly greater than the tissue thickness measured for group 2 (p < 0.001). Seven of the devices from group 3 (78%) developed LAP waveform artifacts. Left atrial pressure waveform artifacts developed at 81 ± 59 days (range 5–154 days) postimplant.

Figure 6A shows gross and subgross images from an ovine with a device that developed LAP waveform artifacts after 140 days of implant (group 3). The tissue covering the sensing diaphragm has an average thickness of 586 μm and is coupled to the adjacent atrial wall. A similar pattern in the histology was seen for the first device implanted in patient 2 (Figure 6B), for which LAP waveform artifacts developed at 35 days postimplant. For this first implanted device (solid outline), the tissue thickness over the sensing diaphragm was 499 μm. Patient 2 was subsequently implanted with a second anchor location A device (dashed outline), which did not develop LAP waveform artifacts. The tissue thickness over the sensing diaphragm for this second device was 266 μm with no evidence of this tissue being coupled to the adjacent atrial wall.

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Discussion

This comparative pathology evaluation demonstrates that the pathology of the LAP sensor from both the canine and the ovine closely approximates the pathology seen in humans. The LAP sensor caused no adverse events when implanted for periods ranging from 20 days to >4.5 years across three species. Gross and microscopic examination demonstrated no excessive host-to-device reaction in either humans or animals. There was also no evidence of active thrombogenesis or embolic events in any of the subjects that followed the required antithrombotic protocol. All the pathologic findings support the long-term safety of the device.

Although ovine were not administered with any oral antithrombotic agents postimplant as a consequence of having a ruminant digestive system, this did result in thromboembolic complications or appear to affect neoendothelial tissue formation over the device. Because ovine have fewer platelet aggregation agonists in comparison with humans and canines, there may be less of a need for using antiplatelet agents in ovine.8

The appearance of the neoendocardial tissue covering the LAP sensor is similar to what is observed for septal closure defect devices.9 Sigler and Jux9 showed that the histopathology seen in humans for a septal defect closure device was similar to the histopathology seen in the ovine model. In comparison with the LAP sensor, septal defect closure devices are significantly larger in size and may contain a nitinol mesh or polyester fabric to promote tissue ingrowth. The degree of tissue coverage and ingrowth seen in septal defect closure devices is more significant than the amount of tissue seen covering the LAP sensor. Septal defect closure devices traditionally require open heart surgery to extract the device safely. In contrast, clinical experience from five patients implanted with the LAP sensor has shown that the LAP sensor may be safely extracted from the tissues encapsulating the device using standard percutaneous techniques for extracting pacing leads.4

Comparative pathology data provided insight into the mechanisms responsible for producing LAP waveform artifacts. Left atrial pressure waveform artifacts were found to more likely occur when the neoendocardial tissue covering the sensor diaphragm is excessively thick (>300 μm) or coupled to the adjacent atrial wall. Under such conditions, the motion of the sensor diaphragm reflects changes in atrial wall tension in addition to fluctuations in left atrial fluid pressure.3 Left atrial pressure waveform artifacts were eliminated by updating the anchor location, such that the sensing diaphragm would protrude an additional 1.5 mm into the left atrium. In addition, implanting physicians were trained to avoid placement of the device via a PFO tunnel and to achieve an orthogonal orientation of the sensor relative to the interatrial septum. Clinical experience from 41 more recent implants of the LAP sensor with the updated anchor location confirmed the absence of any LAP waveform artifacts.3

Although neoendocardial tissue coverage of the sensing diaphragm has no negative impact on the performance of the LAP sensor when it is not thickened (≤300 μm) and not coupled to the adjacent atrial wall, it has the potential to cause a change in the LAP sensor calibration offset without affecting the LAP waveform morphology. Under such circumstances, a correction to the calibration offset can be made using a noninvasive Valsalva calibration procedure, which has been shown to produce accurate LAP measurements that correlate closely (r = 0.98, mean difference 0.8 ± 4.0 mm Hg) with pulmonary capillary wedge pressure measurements.3,10

The time course for neoendocardial tissue encapsulation over the sensing diaphragm may be determined by reviewing the change in LAP measurements over time (Figure 7). It is hypothesized that as neoendocardial tissue grows over the sensing diaphragm, LAP increases from the additional tension being applied by the tissue capsule and that once the diaphragm is completely covered with tissue, there is relaxation of the tissue capsule that causes the LAP to return toward baseline. This entire healing phenomenon lasts approximately 3 months and may be initiated as early as several weeks postimplant and as late as a year postimplant. During this healing interval, LAP measurements may still be accurately obtained by periodic noninvasive recalibration.3,10 For LAP sensors with the updated anchor location, this healing phenomenon is anticipated to occur in <10% of the patients because only a minority of the devices with the updated anchor location become covered with tissue over the sensor diaphragm. Once healing is complete, sensor calibration should remain stable.

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Limitations

The number of available human specimens with devices that have the updated anchor location is limited (n = 2), such that it may be difficult to generalize the conclusions derived based on the human specimens alone. However, because the histopathology was similar between humans and animals for devices with the original anchor location, it is reasonable to hypothesize that the conclusions derived with regard to devices with the updated anchor location from animals are equally applicable to humans. Another limitation of the study is that the surface of the neoendocardial tissue covering the sensor was not characterized to determine whether there were any heparin-like molecules present. Such a finding may explain why there was no thrombus formation over the device.

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Conclusions

This comparative pathology evaluation supports the long-term safety of the LAP sensor when permanently fixated to the interatrial septum. Based on the histopathology observed for subjects implanted with devices that incorporated the original anchor location, it was possible to determine the mechanisms responsible for producing LAP waveform artifacts and make necessary updates to the anchor location and implant guidelines, which resulted in the elimination of LAP waveform artifacts without comprising the safety of the device. Although the early clinical effectiveness data from the HOMEOSTASIS2 trial for the LAP monitoring system is promising, additional clinical evaluation is ongoing in the Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy (LAPTOP-HF) trial to evaluate the effectiveness within a large-scale, randomized, controlled trial setting. The LAPTOP-HF is estimated to enroll up to 730 patients at 75 clinical sites.

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References

1. Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemondynamic monitoring in chronic heart failure: A randomized controlled trial. Lancet. 2011;377:658–666
2. Ritzema J, Troughton R, Melton I, et al. Physician-directed patient self-management of LAP in advanced chronic heart failure. Circulation. 2010;121:1086–1095
3. Troughton RW, Ritzema J, Eigler NL, et al. Direct LAP monitoring in severe heart failure: Long-term sensor performance. J Cardiovasc Transl Res. 2011;4:3–13
4. Pretorius V, Birgersdotter-Green U, Heywood T, et al. An implantable LAP sensor lead designed for percutaneous extraction using standard techniques. Pacing Clin Electrophysiol. 2013;36:570–577
5. Rademaker MT, Charles CJ, Melton IC, et al. Monitoring of heart failure: Comparison of LAP with intrathoracic impedance and natriuretic peptide measurements in an experimental model of ovine heart failure. Clin Sci. 2011;120:207–217
6. Khoury DS, Naware M, Siou J, et al. Ambulatory monitoring of congestive heart failure by multiple bioelectric impedance vectors. J Am Coll Cardiol. 2009;53:1075–1081
7. Roberts A, Trainor KE, Weeks B, et al. Integrated microscopy techniques for comprehensive pathology evaluation of an implantable LAP sensor. J Histotech. 2013;36:17–24
8. Byrom MJ, Bannon PG, White GH, Ng MK. Animal models for the assessment of novel vascular conduits. J Vasc Surg. 2010;52:176–195
9. Sigler M, Jux C. Biocompatibility of septal defect closure devices. Heart. 2007;93:444–449
10. McClean D, Aragon J, Jamali A, et al. Noninvasive calibration of cardiac pressure transducers in patients with heart failure: An aid to implantable hemodynamic monitoring and therapeutic guidance. J Card Fail. 2006;12:568–576

left atrial pressure monitoring; comparative pathology; neoendocardium; integrated microscopy; microgrinding; scanning electron microscopy

Copyright © 2013 by the American Society for Artificial Internal Organs