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A 4-year-old boy had a 15-mm atrial septal defect repaired percutaneously with use of an Amplatzer Septal Occluder. At age 16 years, he presented with a week's history of fever, chills, dyspnea, fatigue, and malaise. Cultures grew methicillin-sensitive Staphylococcus aureus. A transesophageal echocardiogram showed a 1.25 × 1.5-cm pedunculated mass on the left aspect of the atrial septum just superior to the mitral valve, and a smaller vegetation on the right inferior medial aspect of the septum. At surgery, visual examination of both sides of the septum revealed granulation tissue, the pedunculated mass, the small vegetation, and exposed metal wires that suggested incomplete endothelialization of the occluder. We removed the occluder and patched the septal defect. The patient returned to full activity after 4 months and was asymptomatic 3 years postoperatively.
Our report reinforces the need for further investigation into prosthetic device endothelialization, endocarditis prophylaxis, and recommended levels of physical activity in patients whose devices might be incompletely endothelialized. In addition to reporting our patient's case, we review the medical literature on this topic.
The Amplatzer® Septal Occluder (ASO) (St. Jude Medical, Inc.; St. Paul, Minn) is a percutaneous transcatheter device for closing septal defects. It is made of nitinol-titanium (NiTi) memory wire mesh infused with polyester patches that facilitate occlusion and endothelialization. The atrial septal defect (ASD) occluder has a smaller right and larger left disc connected with a waist; the size difference between the discs is 4 mm. The sizes of this ASO are determined by the waist diameter (range, 4–38 mm). The 4-mm waist size has right and left disc diameters of 12 and 16 mm, respectively. All the diameters increase in 1-mm increments. The recommended delivery-sheath sizes are 6F to 12F. The ASO has proved to be a feasible, safe, effective treatment for ASDs, and ASO deployment often replaces surgical intervention.1–6 Sequelae of ASO implantation are device embolization, malpositioning, and fracture; erosion and perforation; cardiac arrhythmias and tamponade; thromboembolism; pericardial effusion; and infective endocarditis (IE).7–11 We describe the very late development of IE in a teenage boy, with findings suggesting incomplete endothelialization beyond any documented occurrence in the medical literature that we found. In addition, we review the topical medical literature.
In July 2010, an athletic 16-year-old boy presented with a one-week history of fever, chills, dyspnea, fatigue, and malaise. At age 4 years, he had undergone percutaneous ASO deployment to close a 15-mm ASD. During the week of his symptoms in 2010, the patient visited the emergency department twice and was treated for pharyngitis with use of 875 mg of oral amoxicillin and 125 mg of clavulanic acid (2×/d for 10 d). His symptoms worsened nevertheless. On his 3rd visit of the week, physical examination revealed splinter hemorrhages in his fingernails bilaterally, petechiae, and evidence of embolic phenomena, so he was admitted to the cardiovascular intensive care unit. The patient's medical history revealed that he had sustained a broken nose one month before symptom onset and had received dental care with no antibiotic prophylaxis 2 months before onset. Specimens from nasal swabs, obtained after antibiotic therapy had begun, grew no organisms. No nasal cultures were obtained.
Laboratory results indicated IE and sepsis. Blood and urine cultures grew methicillin-sensitive Staphylococcus aureus (MSSA). A transesophageal echocardiogram showed a 1.25 × 1.5-cm pedunculated mass on the left aspect of the atrial septum just superior to the mitral valve (Fig. 1), no residual shunting, and trivial mitral and tricuspid valve regurgitation. The patient was given intravenous gentamicin and oxacillin, to which MSSA was susceptible. Urgent surgery to remove the infected ASO and patch the ASD was scheduled, to be followed by 6 weeks of antibiotic agents administered through a peripherally inserted central catheter.
Our surgical approach was through the right atrium. We saw the ASO covered by smooth areas of granulation tissue, vegetation on the periphery of the ASO's inferior medial aspect, and incomplete endothelialization of approximately one quarter of the ASO (Fig. 2). An incision was made through the septum. As we retracted the ASO to inspect the left atrium, we noted exposed wiring for approximately three quarters of the ASO's superior, inferior, and anterior circumference, and we saw a pedunculated mass on the ASO's inferior portion near the mitral valve (Fig. 3). Sections of the exposed wire had no tissue attached, and underneath and around the wire was apparent intimal growth. We removed the ASO and used an extracellular matrix (CorMatrix Cardiovascular, Inc.; Roswell, Ga) to patch the ASD. Gross pathologic examination of the ASO revealed blood clots and fibrotic tissue; no microscopic evaluation of the device was performed to confirm the presence of intimal layers or the endothelialization status.
The patient's 11-day hospital stay was uneventful. We saw him in our clinic twice postoperatively and recommended minimal physical activity for at least 3 months. He visited his cardiologist 2 weeks, 1 month, 4 months, and 9 months postoperatively, and annually thereafter. Routine transthoracic echocardiograms showed persistent, mild right ventricular dilation and a patch without residual shunting or effusions. At the 4-month cardiology appointment, the patient reported the cessation of symptoms and was approved to resume normal activity. As of March 2016, he was asymptomatic and very physically active.
In preliminary animal studies of transcatheter ASD closures, investigators reported complete endothelialization within weeks after implantation and a 100% closure rate at 3 months.12,13 However, in human patients, we and others have observed varying degrees of endothelialization with or without late sequelae.8–10,12–21 The endothelialization status of our patient's ASO was never confirmed by microscopy; nevertheless, we associate this very late IE with his recently fractured nose and dental care and with presumed incomplete endothelialization of the ASO—12 years after device deployment. Our findings of exposed metal wire with no evidence of tissue attachment or fibrin indicated the lack of intimal growth on these sections of the device and suggested incomplete endothelialization.
Other investigators have reported IE immediately after ASO deployment and up to 7 years later.9,11,15,16,18,22 Chen and colleagues19 documented incomplete endothelialization 7 years after deployment, with associated dislodgment of the ASO. In contrast, late IE has been reported despite an ASO's complete endothelialization: small, round vegetations coursed along the circumference of the right atrial disc.9 It is unclear whether incomplete endothelialization acts as an impetus for late adverse sequelae.
Structural components of the ASO might contribute to post-deployment sequelae.23–30 In the ASO for ventricular septal defects, the fixed stainless-steel pin buttons at the center of the ASO discs might interfere with endothelialization and be a staging platform for thrombosis.23 The ASO for ASDs has identical pin buttons.
Another ASO component of focus is its polyethylene terephthalate fabric. The surface tension of polyester fabric promotes fibrin and platelet binding, which increases the ASO's susceptibility to infections.24 Of note, our patient had vegetations in both atria. We found only one other report of late, bilateral IE associated with ASO use.16 These findings might be associated with MSSA's prevalence in device-related infections and its predilection for the left side of the heart.24 The ASO itself might have been a conduit for bacterial seeding and manifestation of the right-sided vegetation.
Another structural element under scrutiny is the ASO's NiTi wire mesh alloy (55% Ni and 45% Ti). In numerous cases of Ni-hypersensitivity reactions, the patients' serum Ni concentrations were elevated after ASO implantation.25–30 Nickel hypersensitivity affects approximately 8.6% of the general population.31 To our knowledge, no one has directly correlated Ni hypersensitivity or elevated Ni concentrations with endothelialization; however, there is a relationship between Ni concentration and cellular functionality.25,32,33 Using tissue cultures, Yang and colleagues32 showed that bare NiTi alloys had higher Ni concentrations with lower endothelial-cell functionality than did a titanium nitride-coated NiTi alloy, via the inhibition of pathways associated with actin cytoskeleton, focal adhesion, energy metabolism, inflammation, and amino acid metabolism. It is well known that cellular microenvironments have an important effect on cellular behavior. Endothelial cell adhesion to NiTi wire mesh appears to be crucial in facilitating cell proliferation and spread.33 There seems to be a temporal relationship between elevated Ni concentrations and intimal formation on the surface of NiTi grafts.25 Whether or not a patient exhibits Ni hypersensitivity, it is reasonable to believe that Ni concentrations after ASO implantation can alter cellular microenvironments and invoke varied responses in cellular behavior, metabolism, and symptom display among individuals, and are perhaps ultimately responsible for observed variances in endothelialization.
Despite the rare occurrences of sequelae, NiTi alloys are popular in medical use because of their elastic and thermal deployment, kink and corrosion resistance, dynamic interference, stress hysteresis, magnetic resonance imaging compatibility, and biocompatibility.34 Investigators have analyzed surface modifications and coatings on NiTi alloys at the molecular level.23,32,33,35,36 Shen and associates33 revealed with statistical significance that nanocoating a NiTi alloy with vascular endothelial growth factor increased endothelial cell migration and proliferation and the release of nitric oxide and prostacyclins, all of which can aid endothelialization. Using nanocoated NiTi can decrease Ni concentrations postoperatively and alter the surface binding characteristics that can lead to cellular-behavior changes at the nanoscopic level.35,36 Musick and colleagues37 designed a self-actuating, self-sensing device, embedded into stent architecture, that monitors levels of endothelial cells on the surface. In clinical application, this sensor's inclusion in prosthetic implants would yield real-time diagnostic information that would help to guide individualized antiplatelet therapy and antibiotic prophylaxis, consequently reducing postoperative sequelae.
Infectious endocarditis is a rare and serious sequela of ASO implantation.5–7,24,38 Despite advances in diagnostic and therapeutic techniques, morbidity and mortality rates in IE remain high. The American Heart Association recommends a 6-month course of antibiotics for patients who are given a prosthetic device for repair of congenital heart defects.38,39 Our experience with our patient raises concerns about the current prophylaxis guidelines, because the recommendations arise from data that assume complete endothelialization within 6 months.39 We found no recommendations for patients in whom endothelialization might be incomplete.
Postoperative physical activity levels of ASO patients appear to be left to the cardiologist's discretion. To our knowledge, the only recommendation for athletic patients who have undergone ASD closure with the ASO is restricted activity for at least 3 months.40 After 3 to 6 months, patients are allowed to participate in all sports unless they display symptoms or abnormalities such as pulmonary hypertension, tachyarrhythmias, myocardial dysfunction, and heart block.40 We restricted our patient's physical activity for at least 3 months; thereafter, his cardiologist determined permissible levels. We found only one account of a relevant sequela associated with ASO use: an isometric-exertion–related cardiac perforation 5 years after ASO implantation.41 The authors did not specify the device's endothelialization status; however, their images suggested that it was complete. The U.S. Food and Drug Administration's database indicates that cardiac perforation, erosion, and rupture are the second most prevalent negative sequelae associated with implanted ASOs.42 We speculate that strenuous physical activity and impacts received during full-contact sports affect the endothelialization process. However, data on the relationship between physical activity and ASO endothelialization are few, so no clear connection can be made with late adverse sequelae.
Appropriate, timely therapy can prevent IE. Many factors potentially hinder the endothelialization process of ASOs and increase the risk for IE. The variety of reported experiences renders it unclear whether endothelialization is the impetus for late sequelae after ASO deployment. We conjecture that structural components of the ASO might affect the endothelialization process and patients' outcomes. Also warranting attention are diagnostic techniques that better enable clinicians to evaluate the endothelialization status of prosthetic implants; reopened debate about prophylactic antibiotic and anticoagulation guidelines for ASO patients; and definition of recommendations for ASO patients' physical activity. In these ways, we can better understand the body's reaction to prosthetic devices, improve device biocompatibility, and mitigate late sequelae.
From: Department of Cardiovascular Surgery, Children's Hospital of Orange County, Orange, California 92868