Inflammatory Response to Epicardial Pacemaker Electrode

Summer High School Advanced Research Program 9 June - 1 August 2014, Los Angeles, USA

Inflammatory Response to Epicardial Pacemaker Electrode

SHSARP Student Jasmine Jan1, Li Zhou2 and Gerald Loeb2

1Medical Device Development Facility, Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, USA

Abstract Pacemaker electrodes require the stability of threshold values in order to effectively stimulate myocardial tissues. Complications occur when inflammation in the stimulating tissue raises threshold values above the initial stimulating threshold value. Thus, determining causes of inflammation and finding the most optimal treatment remains a crucial area of study in the functionality of stimulating electrodes. This study focuses on the histology results of an epicardial pacemaker implantation on a fetal sheep. Literature study of epicardial leads reveals similar inflammatory responses during implantation. Inflammation and fibrosis of stimulating tissues can be attributed to excess mechanical stress of epicardial leads on the myocardial fibers and may be mitigated with steroid-eluting systems in order to compensate for mechanical stress. Another solution of rising stimulation thresholds may be to utilize high charge devices to stimulate fibrous tissue. This paper looks into these issues of a developing epicardial pacemaker device to treat complete heart block in the preterm fetus.

Keywords: Epicardial pacemaker, Inflammation, Mechanical stress, Necrosis, Steroid-eluting systems.

Introduction Inflammation presents complications of pacemaker leads when formation of fibrous connective tissue encapsulates the stimulating electrode. Such complications include heightening of the pacing threshold due to inflammatic fibrosis and increased distance between electrode and excitable tissue. [1,2]

During inflammation, cycles of cellular responses occur that promote blood flow to the injury site. Such cycles include activation of complement proteins and clotting proteins. While complement proteins promote the further release of biochemical factors that attract phagocytes, clotting proteins participate in coagulation, in which plasma proteins form fibrinous meshworks to trap the foreign body to the site of the most phagocytic activity. Additionally, inflammatory cells release cell mediators such as hydrolytic enzymes, oxidants and chemitactic agents that kill surrounding myocytes. Dead myocytes are replaced by fibrocytes, which become active in the formation of fibrous tissue. A temporary fibrin matrix develops in order to fill and close the wounded area. [3] However, in the presence of a persistent foreign body, such as an implant, the matrix


is inhibited from healing. Granulation tissue develops to encapsulate the foreign body in a tight, dense membrane of connective scar tissue. [4] Ultimately, excitable tissue is replaced by this connective scar tissue, increasing stimulation thresholds of the myocardial tissue. [5]

Figure 1. Schematic representation of the course of events in acute and chronic inflammation. (Coleman et al. 1974)

We are developing epicardial pacemaker device to treat complete heart block in the preterm fetus. [6] The device is currently is being tested on ewe and their fetus. A recent post-implantation histology report revealed the electrode path was associated with “mixed inflammatory cell infiltrate, myocardial degeneration, and myocardial mineralization.” These morphological changes resemble the inflammatory responses that quickly lead to fibrosis. Once fibrous tissue forms, the stimulation threshold at the electrode-tissue interface peaks dramatically. [5] While this threshold may plateau, the morphological changes forces stimulation thresholds to remain above the initial threshold. The electrode is unable to stimulate the heart and is rendered useless.

Figure 2. Typical stimulation threshold rise for a standard electrode post implant. The acute peak rise in stimulation threshold is unpredictable and the chronic plateau level is higher than that documented at implantation. (Mond et al.)

Materials and Methods


Electrode Assembly The micropacemaker device is designed for percutaneous implantation in the fetal myocardium through the commonly used intra-uterine cannula. [6] The iridium electrode corkscrew acts mechanically as the screw to allow implantation into the fetal heart, as well as electrically as the stimulating electrode to pace the fetal heart. The electrode is resistance welded to the platinum iridium flexible lead. The entire electrode assembly consists of the corkscrew electrode, the helical flexible lead, and an epoxy reinforcing disk over the welded joint. 2-micron thick parylene-C is used to insulate the entire electrode assembly. Parylene is known to have stability in vivo, making it a desirable insulator for chronically implanted electrodes. [7] The tip of the iridium electrode is masked with clay during parylene deposition, allowing the tip to be uninsulated. This allows the iridium to retain optimal conductive properties necessary to stimulate the fetal heart. The remaining assembly of the device is laser welded to an exposed platinum rod and reinforced with an overcoat of epoxy.

Figure 2. Solid model of rechargeable micropacemaker. (Loeb et al. 2012 )

Fetal Heart Histology The pacemaker was implanted into the fetal lamb at the gestation age of 127 days. Ultrasound guidance and electrocardiography signals were utilized to ensure proper placement of the pacemaker in the fetal myocardium. The fetus was aborted after 5 days, 132 gestational days, and necropsy was completed. Tissues removed at necropsy were shipped to a histology service, where dissected tissue blocks were imbedded in paraffin, sectioned and stained at 5 microns, and evaluated by a veterinary pathologist.

Results The electrode was implanted approximately 3.5 mm into the myocardium. The implant track was associated with mononuclear inflammation, myocardial mineralization, and moderate myocardial necrosis (Figure 3). There was clear inflammation observed in the upper coils of the electrode path. The tissue was mixed with macrophages, lymphocytes


and fewer neutrophils. There was marked inflammation on the left ventriclular wall as well as mild inflammation extending along the epicardial tissues.

Figure 3. Image of fetal heart. The path of the electrode was experienced moderate myocardial degeneration and necrosis (red arrows) with moderate myocardial mineralization (green arrows).

Discussion Literature studies relating to epicardial pacemakers have focused on the mechanical stress exhibited by the stimulating leads. One study comparing the differences between epicardial pacing leads and endocardial pacing leads in conventional pacemakers observed the significance of mechanical stress on the morphology of the heart tissue. [8] In their study, the epicardial implantation site showed thick fibrin deposits surrounding the electrodes due to necrosis and myocardial deformation.


Figure 4. Left: Myocardial necrosis with stretched and deformed myocardial fibers 3 days after implantation Right: Diffuse fibrosis around the site of implantation of the epicardial lead with fibrin deposits around the electrode 18 months after implantation. (Chatelain, P., R. Adamec, and J. N. Cox. 1985) The implantation technique requires the surgeon to rely on limited ultrasound guidance and tactile feedback from the device. The force applied on the heart during implantation of the corkscrew electrode is dependent on the accuracy and precision of the surgeon. Additional force applied by the surgeon may drag and stretch myocardial fibers downwards during corkscrew rotation. This may explain the upward whirling of the myocardial tissues (Figure 4). Whirling of the myocardial tissue may also be attributed to the combined effects of rotation of the electrode and the contracting heart during implantation. Because the electrode is screwed into the myocardium, the device moves in sync with the heart. Therefore tissue stretching should not be expected longitudinally along the axis of the electrode. Whirling of the tissue surrounding the electrode depicts latitudinal stretching of the myocardial tissue. Additional studies are needed to further the understanding of latitudinal stretching of the myocardial tissue.

These studies suggest the inflammatory response is due to mechanical stress and ischemic damage rather than immune reaction to foreign body material. The pattern of damage on the fetal heart seems to be consistent with results from other epicardial leads. Epicardial leads consist of relatively large inert electrodes that are anchored into the myocardial tissue. This ultimately incites inflammatory necrosis and myocardial degeneration during which fibrous tissue formation is inevitable. Various studies have suggested that the inclusion of steroid-eluting systems may attenuate inflammation. [9] Steroids may be used to inhibit cells from releasing threshold raising mediators and inhibiting fibrous capsule formation. Studies have discussed how steroids can improve pacing and sensing thresholds by decreasing fibrous tissue formation and inflammation around the electrode. [10,11] Results from this study indicated pharmaceutical intervention of epicardial pacemaker leads may be a promising solution to treat inflammation of the heart. Furthermore, studies have shown short term and long term benefits of steroid eluting endocardial pacing leads. [12] In the case of the fetal


pacemaker, the device is expected to have a lifetime of 1-3 months in order to support the fetus through gestation. Once the fetus is born, the fetal pacemaker is removed, and a conventional pacemaker is implanted. [6] Thus, the application of steroid-eluting systems should be able to improve pacemaker functionality until the fetus is born. However further investigations must be done to confirm these systems will be the optimal solution for the fetal pacemaker device.

An alternative solution to the rise in stimulation threshold is to utilize higher charge devices that anticipate the rise in stimulation threshold. These high charge devices should be tuned to the stimulating threshold of fibrous tissue, and thus be able to stimulate the heart regardless of inflammation. However, higher charge devices also exhibit additional complications. During implantation, cardiac capture is observed prior to expulsion of the device. Cardiac capture observed from low charge devices ensure the device is properly inserted in the myocardial tissue. If the device is implanted tangentially to the heart, fibrous pericardial tissue will not be stimulated and can thus indicate improper placement of the device. Because high charge devices have the ability to stimulate the fibrous pericardium, cardiac capture will be observed when the electrode contacts the pericardial wall falsely indicating proper implantation of the device. Thus further studies must be conducted to find the optimal solution to inflammatory responses and rising threshold values.

Acknowledgements I would like to personally thank Dr. Gerald Loeb for accepting me into his lab. I would also like to thank Li Zhou for incredible mentorship and support during this study. Additionally, I would like to thank Dr. Joe Cocozza and Ms. Diana Sabogal for all the work that they have done for this program. Lastly, I would like to thank WindSong Trust for its generous support of the SHSARP Program.

References [1] Karpawich, Peter P., et al. "A new low threshold platinized epicardial pacing

electrode: Comparative evaluation in immature canines." Pacing and Clinical Electrophysiology 11.8 (1988): 1139-1148.

[2] Ripart, Alain, and Jacques Mugica. "Electrode Heart Interface: Definition of the Ideal Electrode." Pacing and Clinical Electrophysiology 6.2 (1983): 410-421.

[3] Anderson, James M., Analiz Rodriguez, and David T. Chang. "Foreign body reaction to biomaterials." Seminars in immunology. Vol. 20. No. 2. Academic Press, 2008.

[4] Coleman, D. L., R. N. King, and J. D. Andrade. "The foreign body reaction: a chronic inflammatory response." Journal of biomedical materials research 8.5 (1974): 199-211.

[5] Mond, Harry G., and Kenneth B. Stokes. "The Electrode Tissue Interface: The Revolutionary Role of Steroid Elution." Pacing and Clinical Electrophysiology 15.1 (1992): 95-107.


[6] Loeb, Gerald E., et al. "Design and Testing of a Percutaneously Implantable Fetal Pacemaker." Annals of biomedical engineering 41.1 (2013): 17-27.

[7] Loeb, Gerald E., et al. "Parylene as a chronically stable, reproducible microelectrode insulator." Biomedical Engineering, IEEE Transactions on 2 (1977): 121-128.

[8] Chatelain, P., R. Adamec, and J. N. Cox. "Morphological changes in human myocardium during permanent pacing." Virchows Archiv A 407.1 (1985): 43-57.

[9] Fortescue, Elizabeth B., et al. "Comparison of modern steroid-eluting epicardial and thin transvenous pacemaker leads in pediatric and congenital heart disease patients." Journal of Interventional Cardiac Electrophysiology 14.1 (2005): 27-36.

[10] Johns, James A., et al. "Steroid-eluting epicardial pacing leads in pediatric patients: encouraging early results." Journal of the American College of Cardiology 20.2 (1992): 395-401.

[11] Preston, Th A., and R. D. Judge. "Alteration of pacemaker threshold by drug and physiological factors." Annals of the New York Academy of Sciences 167.2 (1969): 686-692.

[12] Sutton, Richard, and Sema Guneri. "The impact of steroid eluting leads on long term pacing in the atrium and ventricle." Eur JCPE 1 (1991): 10-5.

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Inflammatory Response to Epicardial Pacemaker Electrode