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The Evolving Role of the Total Artificial Heart in the Management of End-Stage Congenital Heart Disease and Adolescents

Ryan, Thomas D.; Jefferies, John L.; Zafar, Farhan; Lorts, Angela; Morales, David L.S.

doi: 10.1097/MAT.0000000000000156
Review Articles

Advances in medical therapies have yielded improvement in morbidity and a decrease in mortality for patients with congenital heart disease, both surgically palliated and uncorrected. An unintended consequence is a cohort of adolescent and adult patients with heart failure who require alternative therapies. One intriguing option is placement of a total artificial heart (TAH) either as a bridge to transplant or as a destination therapy. Of the 1091 Jarvik-7 type TAH (Symbion, CardioWest and SynCardia) placed between 1985 and 2012, only 24 have been performed in patients with congenital heart disease, and a total of 51 were placed in patients younger than 21. At our institution, the SynCardia TAH was implanted in a 19-year-old patient with cardiac allograft failure because of chronic rejection and related multisystem organ failure including need for hemodialysis. Over the next year, she was nutritionally and physically rehabilitated, as were her end organs, allowing her to come off dialysis, achieve normal renal function and eventually be successfully transplanted. Given the continued growth of adolescent and adult congenital heart disease populations with end-stage heart failure, the TAH may offer therapeutic options where previously there were few. In addition, smaller devices such as the SynCardia 50/50 will open the door for applications in smaller children. The Freedom Driver offers the chance for patients to leave the hospital with a TAH, as does the AbioCor, which is a fully implantable TAH option. In this report, we review the history of the TAH and potential applications in adolescent patients and congenital heart disease.

From The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.

Submitted for consideration May 2014; accepted for publication in revised form August 2014.

Disclosure: David L.S. Morales is a proctor for SynCardia, a member of the Berlin Heart CEC Committee, and has received travel reimbursement from SynCardia, Berlin Heart and Thoratec. Thomas D. Ryan, John L. Jefferies, Farhan Zafar and Angela Lorts have no conflicts of interest to declare.

Correspondence: Thomas D. Ryan, MD, PhD, The Heart Institute, Cincinnati Children’s Hospital, 3333 Burnet Avenue, MLC 2003, Cincinnati, OH 45229. E-mail: thomas.ryan@cchmc.org.

Over the past several decades, advances in medical and surgical therapies have yielded dramatic improvements in morbidity and reduced mortality for several childhood diseases. Because of these successes, there is now a generation of aging patients encountering previously unseen complications. One dramatic example is patients with congenital heart disease, both surgically palliated and uncorrected, who develop end-stage heart failure. According to the Congenital Heart Public Health Consortium (www.chphc.org), in the United States there are an estimated 2 million people living with congenital heart disease, including approximately 959,000–1.5 million adults. This encompasses “a substantial number of young adults with single ventricle physiology, systemic right ventricles or complex intracardiac baffles.”1 Familial and acquired cardiomyopathies constitute another group of patients at risk for heart failure, and whose numbers are increasing because of improved recognition, diagnosis and early therapy.

When medical treatment is inadequate in the adult congenital heart disease (ACHD) patient with heart failure, surgical options are considered. These may include surgical revision or cardiac transplantation.2 Only 3000–5000 heart transplants are performed worldwide each year, with approximately 3% in ACHD.3 Not all patients are appropriate candidates for transplantation as some may have end-organ dysfunction requiring concurrent therapies not compatible with transplant, inability to tolerate the necessary immunosuppression or high panel reactive antibodies (PRA).

Viable alternatives are needed for the patient with end-stage heart failure due to congenital heart disease that is ineligible for a further palliative surgical procedure or those unable to wait for a donor to become available. One intriguing option is placement of a total artificial heart (TAH) as a bridge to transplantation. The concept of mechanical circulatory support (MCS) as a bridge to transplant is familiar territory, with approximately 20% of all candidates temporized with some form of MCS.3 There are several options available,4 and overall the number of MCS devices implanted is now approaching, if not surpassing, the number of transplantations performed.5 The time gained with MCS may allow reversal of end-organ dysfunction by providing adequate cardiac output, or time for treatment of elevated PRA in the highly sensitized patient.

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History of the Total Artificial Heart and Current Use

The story of the artificial heart is a fascinating narrative stretching back over 60 years and including some of the pioneers of modern medicine (Table 1). Although the exact origin of MCS is open to interpretation, the animal experiments by Glenn and Sewell6 published in 1950 showed proof of concept by supplying blood to the pulmonary artery with a mechanical pump and bypassing the right ventricle. Several attempts were made to use this technology in patients, but the first successful use of MCS was undertaken by Dodrill7 using the “Michigan Heart” in 1952, followed shortly thereafter by the groundbreaking work of Gibbon8 in 1953 with the first heart–lung machine used during the repair of an atrial septal defect. Finally, the first true TAH was implanted in a dog by Akutsu and Kolff9 in 1957.

Once the TAH had proven application, its use in patients was the next goal. In 1969, Cooley and Liotta10 used a TAH to support a man suffering end-stage heart failure for 64 hours until a donor heart was implanted. The modern era of the TAH was ushered in by the work of Kolff et al11 when, in 1975, a calf was supported for 18 days with a Jarvik-type TAH, the precursor to current designs. This was followed in 1982 by Barney Clark’s 112 days of support with the Jarvik-712 and successful use of the device to bridge a patient to heart transplant in 1985.13 The Jarvik-7, in 100/100 (ml per artificial ventricle) and 70/70 capacities under the name Symbion, was granted an investigational device exemption (IDE) and was implanted in 198 patients from 1985 to 1991.14 With loss of the IDE in 1991, there was a halt of implantations in the United States until the 70/70 version was granted a new IDE in 1993 under the name CardioWest. Starting in 2001, the device was marketed as SynCardia and was given Federal Drug Administration (FDA) approval in 2004 after a 10-year clinical trial.23

Since 1986 greater than 1000 TAH of the Jarvik-7 type have been implanted at more than 90 institutions worldwide. There has been a steady increase in annual use over that time, with 433 TAH implantations from 2010 to 2013, including 161 in 2013 alone, as compared with 835 in the 25 years from 1985 to 2009 (direct communication, SynCardia Systems Inc.). The indications for implantation include severe biventricular failure, intractable arrhythmias, postinfarction ventricular defects unable to be repaired, ventricular failure with prior mechanical valve replacement, extensive ventricular thrombus, cardiac allograft failure, ascending aortic aneurysm or dissection with concurrent heart failure, and failure of other types of mechanical support.15,24,25 The ability to rescue the patient and prevent multisystem organ failure is dependent on the restoration of blood flow. The standard ventricular assist device (VAD) generally has a maximum cardiac output of 6–7 L/min and placement may unmask right ventricular dysfunction. The 70/70 TAH not only supports both pulmonary and systemic circulation but also can achieve cardiac output of greater than 9 L/min at a significantly lower central venous pressure (CVP).23 When resuscitating end-organs, it is the low CVP provided that is the key difference from left VAD (LVAD) therapy or even early postoperative heart transplantation. Risk factors for poor outcome in LVAD, including right heart failure, elevated CVP and various markers of multisystem organ failure, have not been found to be significant risk factors in the TAH.26

In contrast to the Jarvik devices that require externalized drivelines, the AbioCor by Abiomed, originally described in a series of papers in 1993,16–18 is a completely implantable, electrohydraulic device capable of providing 8–10 L/min of cardiac output. After early work in a bovine model,19 an IDE was granted in 2001 and the first human implantation was performed by Gray and Dowling that same year.20

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Potential Use of the Total Artificial Heart in the Management of End-Stage Congenital Heart Disease and Adolescent Patients

Limited citations can be found regarding use of TAH in pediatric and ACHD patients. These include pediatric and adolescent patients with biventricular heart failure27,28; a 15-year-old with left ventricular thrombus in the setting of heart failure29; and 3 patients with “valvular and congenital re-operations.”30 Two applications in failing single ventricle palliation are in the literature, a 17-year-old with congenitally corrected transposition of the great arteries (CCTGA) and a failing systemic ventricle,31 and a 13-year-old with pulmonary atresia and intact ventricular septum who developed plastic bronchitis and severe circulatory failure.32 Both patients were successfully bridged to heart transplantation.

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TAH Experience to Date in the Adolescent Patient Population

Of the 1091 TAH implanted worldwide from 1985 to 2012, 51 (4.7%) were in patients under the age of 21, regardless of diagnosis (Table 2; direct communication, SynCardia Systems Inc.). The implantations took place at 21 institutions around the world (United States, 13; Europe, 5; Canada, 2; Australia, 1), with 16 being the most implanted in a single institution. Median age of this group was 18 (13–21), and 20% were female. Etiologies of heart failure included cardiomyopathy in 35 patients (68.6%) (dilated, 21; hypertrophic/restrictive, 7; postpartum, 2; ischemic, 2 and other, 3); congenital heart disease in 6 patients (13.3%); myocarditis in 2 patients; graft rejection in 2 patients and other in 6. Total support time was 3093 days with a median time of 19 days (1–605). Only five (10%) patients required support more than 6 months. Overall survival was 69% (35/51) over the entire time period. Over the last 10 years survival was better, 71% (17/24), compared with initial experience of 66% (18/27), but lacks statistical significance (p = 0.5). Competing outcomes analysis at 2 months demonstrates 71% of patients had a positive outcome (26% still on the TAH, 45% transplanted) and 29% had died (Figure 1A).

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TAH Experience to Date in the ACHD Population

In the ACHD population, which includes some of the same patients in the under-21 group, 24 (2.2%) devices were implanted in patients of all ages, with 6 (25%) in patients 18-years-old and younger (Table 2; direct communication, SynCardia Systems Inc.). The implantations took place at 16 institutions around the world (United States, 9; Europe, 5; Canada, 2). Patient median age was 28, (13–56), and 25% were female. Total days of support were 1476 with a median of 24 days (1–359). Overall survival to hospital discharge was 62%, with 100% survival in adolescent patients with congenital heart disease. There were nine mortalities, of which eight (89%) occurred in the first month of support. The cause of death was multisystem organ failure in five patients, pulmonary hemorrhage in one and was not reported in three. Competing outcomes analysis at 2 months demonstrates 67% of patients had a positive outcome: 34% were still on the TAH, 33% were transplanted and 33% had died (Figure 1B).

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Progressive Heart Failure in Patients With Congenital Heart Disease

Patients requiring significant anatomical corrections and MCS.

A number of patients with surgically corrected or palliated congenital heart disease are left with abnormal anatomy that makes placement of a VAD difficult or impossible. Factors such as artificial conduits, valvular insufficiency and residual shunts may lead to complications with inflow or outflow of the device. In the past, many would repair residual defects then place a VAD or biventricular assist device (BIVAD). However, the morbidity/mortality profile will be different than VAD placement alone, and it may be better to place a TAH initially. In addition, because the Jarvik device can be separated (i.e., right-side and left-side pumps) it is amenable to use in complex congenital heart defects. This was the case for a 17-year-old patient with CCTGA who developed biventricular dysfunction, severe aortic insufficiency and significant obstruction of the conduit providing pulmonary blood flow. Because the SynCardia could be separated into two pumps, manipulation of its profile and implantation in parallel fashion with restoration of adequate systemic and pulmonary blood flow was possible.31 The TAH does have basic anatomic requirements, including need for two atrioventricular valve annuli. If one annulus is small, enlargement is possible. Use of TAH when no right-sided atrioventricular annulus is present requires the creation of a capacitance chamber for systemic venous return and is a challenging proposition.

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The failing Fontan.

Since it was first described in the 1970s the Fontan operation and its modifications have offered palliation to single ventricle patients. Despite the fact that it remains the best surgical palliation for this population, the Fontan circulation represents an abnormal hemodynamic state with significant problems both in the short-term and long-term. These complications include elevated CVP, the need for staged surgical procedures, pulmonary arteriovenous malformations, dysfunction of the single ventricle and lymphatic derangements such as persistent chylothorax, protein-losing enteropathy and plastic bronchitis.2,33

Although the Fontan operation has allowed stable circulation for a generation of single ventricle patients, there is a growing concern with the “failing Fontan.” The original atrial-pulmonary connection has been shown susceptible to atrial dilation, arrhythmias and baffle thrombus.34 One solution is conversion of the Fontan to either a lateral tunnel or extracardiac conduit configuration. For the patient early in the process of failure, before significant end-organ dysfunction, a Fontan conversion surgery is a valid solution for atrial-pulmonary Fontan with atrial arrhythmias or mild symptoms and other Fontan types with anatomical issues.34 Survival after orthotopic heart transplantation performed for the failing Fontan has been reported as worse than outcomes than for other indications, particularly for Fontan failure soon after the surgery is performed.2,35 The first use of MCS in a failing Fontan was reported in 2005,36 and a recent report on the Berlin Heart EXCOR in single ventricle patients describes use in five patients status post Fontan.37 Biventricular support using Berlin EXCOR has been reported in both a 4-year-old with plastic bronchitis and failing Fontan physiology,38 and in a 19-year-old with end-stage cardiorespiratory failure who could not accommodate BIVAD implantation in the chest.39 There are also nonsurgical strategies, including medications and nocturnal noninvasive respiratory support, but a normal CVP is required and arrhythmias must be under control.

In the failing Fontan TAH offers an option that provides two ventricles worth of cardiac output but is not affected by many of the anatomical constraints or limitations. In the late failing Fontan, with evidence of end-organ dysfunction but before irreversible pathology, outcomes for transplantation are similar to those for other similarly aged patients.40 For Fontan failure with signs of plastic bronchitis, cirrhosis, or protein-losing enteropathy, transplantation may not be an option, and TAH may represent the best possible solution. The use of TAH may allow improvement or reversal of these symptoms and ultimately make a patient eligible for transplantation, or once approved for that application could serve as destination therapy (DT). The potential to reverse potentially end-stage liver dysfunction (“ cirrhosis”) or renal failure secondary to Fontan failure is perhaps possible with the TAH since, unlike other forms of chronic MCS, it provides supraphysiologic cardiac output with a low CVP.

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Intractable Arrhythmias

Unrelenting arrhythmias can detrimentally affect cardiac function and may be fatal. The causes range from genetically determined channelopathies to myocardial injury such as viral myocarditis or coronary artery disease. Extracorporeal membrane oxygenation has been used as a temporizing measure and as bridge to transplant.41 Certain types of congenital heart disease, such as Ebstein anomaly and CCTGA, are at increased risk for arrhythmia, and a number of channelopathies are identified in pediatric and adolescent patients. Any surgery involving manipulation of the atria or ventriculotomy produces a substrate for abnormal rhythms. When medical therapy, catheter-based, or surgical interventions fail to control the arrhythmia, an LVAD alone may not be appropriate if the right ventricle is equally affected. In these scenarios, TAH may be a life-saving consideration in the appropriate patient.

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Cardiac Tumors and Other Malignancy

Cardiac tumors are a rare occurrence, ranging from benign lesions to high-grade malignancies. The vast majority are myxomas, which are cured with resection, or sarcomas with a less favorable outcome. The most common types in the adolescent population are fibromas and rhabdomyosarcomas. In the case of cardiac sarcoma, palliative surgery may be undertaken to relieve obstruction but complete resection is rare. Even in the case of benign lesions the mass can be too large for resection and may require transplantation as the only viable option.42

Heart transplantation is contraindicated in the case of active malignancy or ongoing chemotherapy. Heart failure may occur as a result of the malignancy or, more commonly, as a consequence of radiation and chemotherapy, specifically anthracyclines.43 A patient with active malignancy is not eligible for cardiac transplantation and, by convention, needs to be in remission for 2 years before being considered. Given the improving survival for childhood cancers,43 TAH placement could act as a bridge during treatment until the patient is a suitable transplant candidate.

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Cardiomyopathy, Myocarditis and Allograft Failure

Cardiomyopathy in adults is epidemiologically different from that found in pediatric and adolescent patients. Where the former is commonly due to ischemic heart disease the latter is infectious, genetically driven, associated with another systemic illness or most often idiopathic.44 In certain cases, such as restrictive cardiomyopathy, 5-year survival is dramatically improved with use of transplantation as the treatment modality.45 When a patient presents with end-organ dysfunction or contraindication to immunosuppression, transplantation may not be an immediate option. Cannulation for LVAD is often challenging due to small left ventricular volumes and obstruction to the inflow cannula with systole. The TAH offers the benefit of transplantation without the need for immunosuppression. Simply placing BIVAD may not be the appropriate answer, as survival is worse than for LVAD alone.46

Once a patient has undergone transplantation they are at risk for a number of untoward outcomes such as severe rejection, end-stage graft vasculopathy or post-transplant lymphoproliferative disease (PTLD).47 At present, the only treatment for graft vasculopathy is retransplantation. The chemotherapy required to treat PTLD would be a contraindication to retransplantation. In the case of severe rejection, the intense immunosuppression required presents high infectious risk should LVAD support be indicated, and ultimately may not control the rejection. Patients bridged to retransplant with MCS actually do worse than patients not bridged at all, particularly if the retransplant occurs within 1 year of the primary transplant.48 This is because of a number of factors, but most likely the increased risk of infection in an immunosuppressed patient with a chronic foreign body. In addition, patients with a chronic rejection often exhibit restrictive physiology that is unresponsive to inotropic treatment, and renal failure with poor response to attempts at diuresis because of elevated CVP and immunosuppressive regimens. Implantation of TAH would provide adequate cardiac support while allowing a lower CVP and discontinuation of immunosuppression.

At our institution, we implanted SynCardia 70/70 in a 19-year-old woman with history of renal clear cell carcinoma requiring nephrectomy and chemotherapy, with subsequent chemotherapy-induced cardiomyopathy requiring heart transplantation. Eight years post-transplantation she developed severe restrictive physiology due to chronic allograft rejection. Because of multisystem organ dysfunction, including renal failure requiring continuous veno-venous hemodialysis, rapidly deteriorating clinical status and being highly sensitized against human leukocyte antigens, she required rehabilitation before being an eligible transplant candidate. Initially, she had progression of renal failure with a period of anuria lasting approximately 6 weeks and requiring aquapheresis (Figure 2). Within 8 weeks of SynCardia implantation she had return of normal plasma creatinine and was listed for heart transplantation. After 1 year of support she underwent successful heart transplantation. This period of excellent cardiac output and low CVP allowed us to find an appropriate donor in a highly sensitized patient who otherwise might not have survived because of long waitlist time.

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Other Clinical Scenarios

Several other clinical scenarios lend themselves to application of the TAH in the ACHD and adolescent populations. Patients with heart failure who require time and rehabilitation before eligibility for transplantation include those receiving cardiotoxic therapies; those with high PRA profiles due to multiple sensitizing events; those with pulmonary hypertension in the setting of heart failure and patients with right heart failure in which upstream organs suffer from chronically elevated CVP. With recent approval by the FDA for the SynCardia 70/70 as a Humanitarian Use Device in patients who are not transplant eligible, the TAH may serve both as a bridge to transplantation and an option for DT.

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The Future: Smaller Devices and Support Outside of the Hospital

The primary limitation to use the TAH in adolescent and pediatric populations is size of the devices. The approved lower limit for patient size in SynCardia is body surface area (BSA) 1.7 m2, or that of an average adult woman. There is also a required minimum 10 cm distance from the T10 vertebrae body anterior surface to the sternum. Regardless, in one series the device was successfully implanted in patients with BSA 1.5–1.7 m2 with results similar to patients >1.7 m2 as long as the patients had dilated cardiomyopathy which left a large footprint for device placement.49 The 19-year-old patient described above was below the approved BSA and T10-sternum distance, yet the device was placed as predicted by a “fit study” in which three-dimensional reconstructions of the thorax and SynCardia were modeled to find the appropriate orientation. These reconstructions also allow examination of the orientation of the native ventricles and allow for virtual manipulation of the device, including separating the systemic and pulmonary pumps, to find an appropriate configuration in complex congenital anatomy. This was the case in the previously described patient with CCTGA31 and would also be of use in patients with situs inversus. For cardiomyopathy, specific diagnosis makes a difference and in a patient with dilated or restrictive type, the enlarged chambers may produce a relatively large implantation pocket in a small patient. Using personalized data for patients, as opposed to one-size-fits-all absolute parameters, will allow us to push the envelope regarding patient selection and open use of the TAH to more patients.28 SynCardia is currently developing a 50/50 pump that, upon approval, will be intended for use in patients as small as BSA 1.2 m2, and is planning an IDE study that will have adult and pediatric patient cohorts and compassionate use arms.

Another limitation of TAH technology is that the patient is tethered to a large control unit. In 2010, the FDA approved a 13-pound piston-driven pneumatic compressor carried in a backpack and with a 3-hour battery life. Case reports have documented use of the Freedom Driver by patients discharged to home with the device, as was our patient.21,50 This is particularly important for patients who may have a prolonged course on the TAH while awaiting transplantation or if in the future the device is used for DT. The AbioCor fully implantable TAH is another option for support outside of the hospital. However, with its 18-month battery life and large size, it has seen limited use22 and to date there are no reports in pediatric, adolescent or ACHD populations. A smaller version known as the AbioCor II is under development.

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Conclusion

The number of heart transplantations performed worldwide has been relatively unchanged since it peaked in the 1990s while the number of patients on the wait list continues to increase.3 With the aging population of ACHD patients this number will continue to grow with many patients developing end-stage heart failure. Indeed, patients who avoided transplantation as children may now need alternate treatment strategies. These should include consideration of the TAH as a bridge to transplant or in the future as DT. Recent data in adult patients show similar outcomes when comparing biventricular VAD support and TAH.51 However, TAH allows physicians to offer treatment to patients who did not have good MCS options such as the failing Fontan, chronic heart transplant rejection including those who are highly sensitized, chronic right ventricular failure with an LVAD in place, biventricular failure, cardiac tumors, intractable arrhythmias, patients with active malignancy, restrictive physiology or significant end-organ dysfunction. Physicians are also allowed a new creativity in application of MCS to pediatric and ACHD patients. Given the growing number of young patients that currently have, or at risk for heart failure and with improvements in device size and availability, opportunities to use the TAH in the pediatric age groups will dramatically change the approach to these populations.

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Limitations

The experience of TAH use in pediatric and ACHD patients is limited. As such, we used our experience with a single patient and the collected unpublished data from one company to draw conclusions about TAH use in these populations.

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Acknowledgments

The authors thank Aimee Gardner, CCP, and Megan del Corral, RN, for technical support and input during preparation of the manuscript.

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mechanical circulatory support; total artificial heart; heart transplantation; adult congenital heart disease; pediatrics

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