Previous challenges and current progress–the use of total artificial hearts in patients with end-stage heart failure

KEYWORDS:

• Total artificial heart
• heart transplant
• heart failure
• mechanical circulatory device
• SynCardia
• mechanical circulatory support
• BiVACOR
• Cleveland Heart
• CARMAT
• AbioCor

1. Introduction

The magnitude of unmet clinical demand for patients needing a heart transplant has motivated scientists and clinicians for over half a century to develop an implantable mechanical replacement. In the USA, 400,000 people die from heart failure every year, while clinicians are only able to provide 2000–2500 transplants per year [1,2]. While some patients with left-sided heart failure can receive a left-ventricular assist device (LVAD) to augment cardiac output, many patients do not qualify for an LVAD. Thus, patients in end-stage heart failure who do not qualify for an LVAD or are unable to obtain a heart transplant would benefit from a durable, self-contained, and biocompatible total artificial heart (TAH).

The ability of the heart to perfuse the body is deceptively simplistic as many challenges have been revealed in pursuit of a TAH. Most efforts have focused on creating TAHs with pulsatile flow, composed of two volume-displacement pumps connected to unidirectional inlet and outlet valves. TAHs with self-contained actuation mechanisms have been devised; but all have been limited by poor durability. Some TAHs have performed well in chronic animal studies and even in small clinical pilot studies. Encouraging results notwithstanding, the only artificial heart that has been implanted with any frequency, the SynCardia TAH, employs an external pneumatic actuation mechanism that is connected to the device via a pair of transcutaneous air hoses. As a result, this device is used almost exclusively as a bridge to transplantation (although a new ‘Freedom Driver’ affords the patient more mobility compared to the traditional C2 hospital driver). However, several TAHs are being developed that utilize self-contained rotary technology and have shown promise in addressing some of the current challenges for destination therapy. Others harness technology similar to earlier TAH predecessors with volume-displacement pumps but contain blood-contacting surfaces lined with biological materials. TAHs will continue to be a treatment option for patients with end-stage heart failure when cardiac transplants are not available (as a bridge to transplantation). However, some TAHs show promise as a destination therapy as new technologies emerge.

2. The beginnings of TAH technology

Leonardo da Vinci was one of the first to describe the concept of an artificial heart in the fifteenth century; however, intense research in this field was not realized until the twentieth century with Akutsu and Kolff’s successful implantation of a TAH in an animal [3]. This sparked a boom in the research of TAHs that culminated in Michael DeBakey’s successful request to US President Lyndon B. Johnson for financial support for a TAH program, which was established in 1964. President Johnson’s challenge was to develop a fully functional TAH by the time humans set foot on the moon. On 4 April 1969, 3 months before the first lunar landing, Denton Cooley, of the Texas Heart Institute, Houston, TX, USA, became the first surgeon to implant a TAH in a human [4].

On the basis of the initial clinical experience with a TAH at Texas Heart Institute, Akutsu and colleagues working in Texas Heart Institute’s Cullen Cardiovascular Research Laboratory developed the Akutsu III artificial heart. Meanwhile, Kolff and Jarvik had been developing the Jarvik 7 TAH [5]. However, the advent of cyclosporine in 1983 led to a shift in focus from developing permanent replacements for failing hearts to bridging patients with biventricular failure to heart transplantation. Subsequently, the Jarvik 7 experienced several improved iterations and name changes from the Symbion Artificial Heart, the CardioWest TAH, and the SynCardia temporary TAH [6].

The use of external drivers for the SynCardia temporary TAH has several advantages over internal drivers. By integrating the electronic components and most of the mechanical complexity in the paracorporeal pneumatic compressor, the components that need to be implanted could be decreased in size and mechanistically simplified, which facilitated implantation in smaller patients. In addition, those parts that are most likely to fail because of cyclic fatigue are outside the body, where they can be closely monitored and promptly exchanged. At present, external drivers are exchanged preemptively every 6–12 weeks. The flexible components implanted in the chest – the pneumatically actuated diaphragms – also have limited durability because they must flex between 30 and 50 million times per year. The transcutaneous air hoses are an important physiological liability because of the increased incidence of ascending driveline infections in patients undergoing long-term support. Although device infections have caused few deaths in patients awaiting transplantation, the mean duration of SynCardia support is 15–90 days at different centers. In a large series of 171 patients, 60% were supported by the SynCardia device for <2 weeks, and the average duration of support was 24 days. A total of 37% of patients experienced severe infectious complications necessitating urgent transplantation. Nevertheless, various iterations of the SynCardia temporary TAH have subsequently been implanted in >1300 gravely ill patients, around 80% of whom have been successfully bridged to heart transplantation (1-year survival is 70%). A total of 241 patients have survived for more than 6 months, 92 for more than 1 year, 16 for more than 2 years, and 3 for more than 3 years; the longest duration of bridging so far is 1374 days [7].

Although the results of heart transplantation continued to improve after the introduction of better immunosuppressive agents, the supply of donor hearts remained a limiting factor. The National Heart, Lung, and Blood Institute (NHLBI) increased funding in 1988 to develop a completely implantable TAH with the aim of producing a practical long-term heart-replacement device. Many ambitious attempts were made to develop durable, self-contained, volume-displacement TAHs with internal actuation mechanisms that eliminated the need for an external driver and percutaneous drivelines or pneumatic hoses. The resulting devices included the Sarns-3M TAH (3M Health Care, St. Paul, MN, USA, in conjunction with the Pennsylvania State University, University Park, PA, USA), the Nimbus TAH (Nimbus, Rancho Cordova, CA, USA, in conjunction with the Cleveland Clinic, Cleveland, OH, USA), the AbioCor®TAH (ABIOMED, Danvers, MA, USA, in conjunction with Texas Heart Institute and the Jewish Hospital in Louisville, KY, USA), and the electrohydraulic TAH (developed at the University of Utah, Salt Lake City, UT, USA).

Each of these devices met NHLBI criteria and was powered by transcutaneous energy transfer systems without the need for a percutaneous driveline. An implanted battery provided continuous operation in the event of transient disconnection of the transcutaneous energy transfer system. In 2001, Gray, Dowling, and others implanted the ABIOMED AbioCor® TAH in 14 patients at four US centers. Three died in the perioperative period from hemorrhage (n = 2) or air embolism (n = 1), and six patients died from multiorgan failure within the first 9 months. The remaining five patients survived for 9–15 months but died from complications related to stroke, infection, or organ failure, except the longest surviving patient, in whom the device failed because an internal flexible membrane ruptured [8]. While ABIOMED subsequently refined the device to decrease the overall size and the US FDA approved the refined device for use in humans, the project was deemed commercially unviable and prohibitively difficult and was discontinued in 2007.

3. TAH challenges

The development of a self-contained, fully implantable TAH is associated with several challenges. Achieving adequate durability (>5 years), minimizing thromboemboli and hemolysis, maintaining pulmonary–systemic circulatory balance, and accommodating the limited constraints in women and small adolescents and children are examples.

Maintaining pulmonary–systemic balance of a TAH is problematic because the entire output of the right ventricle is pumped through the pulmonary circulation to the left atrium, but the same is not true of the left ventricular output. Consequently, the output of the left ventricle might be 10–15% greater than that of the right ventricle. If this balance is not properly maintained, the lesser-functioning side will rapidly develop atrial hypertension. Left atrial hypertension results in pulmonary edema and respiratory failure. Right atrial hypertension results in anasarca, ascites, and renal and hepatic insufficiency. Efforts to decrease excessive atrial pressure in a TAH recipient who develops pulmonary–systemic imbalance can result in suction events on the low-pressure side, which might lower cardiac output. A mechanism that autonomously assesses and maintains proper balance is essential.

4. Future TAH technology

The AbioCor® TAH was the only fully implantable, self-contained TAH to be implanted in humans that utilized a mechanism to equalize pulmonary and systemic flow. After ABIOMED stopped the AbioCor program, the prospect of a totally implantable, permanent mechanical heart-replacement device seemed very far off. To address some of the unsolved challenges in the field, Golding and colleagues began focusing on continuous-flow rotary blood pumps. Rotary blood pumps were proposed to solve the durability challenges and the space constraints intrinsic to volume-displacement pulsatile output pumps but were initially viewed with skepticism relating to the absence of a physiological pulse. In 1987, Qian and colleagues attempted to create a single-device rotary TAH intended for long-term cardiac replacement, but could not adequately balance the left and right circulation [9]. Encouraged by the success of continuous-flow LVADs in supporting patients with advanced heart failure over the last 15 years, several groups have begun to focus intently in the current era on rotary blood pump technology to craft the next generation of TAH. BiVACOR (Houston, TX, USA) [10] and Cleveland Heart (Cleveland, OH, USA) [11,12] each have developed rotary TAHs that leverage the advantages of centrifugal pumps. These rotary pumps lacked any mechanical bearings or other sources of mechanical wear and no flexible components or valves, and both utilize a two-sided impeller, with blades on one face that accelerate the systemic blood and on the other face that pump pulmonary blood. These devices are smaller, more energy efficient, and, in theory, much more durable than the devices that predate them. Moreover, each has an intrinsic mechanism that allows systemic and pulmonary balance to be adjusted and maintained autonomously.

Chronic testing of the Cleveland Heart in animals is ongoing, but 90-day survival has been reported in two animals [13]. Human fitting studies have also been conducted [14]. BiVACOR chronic studies in calves have involved nine implantations, with greater than 30-day survival in three calves. During in vitro testing, the demonstrated maximum capacity of 23 l/min at 100 mmHg and, when operated with speed modulation, can produce flow pulses of 0–18 l/min and pulse pressures of 120/80 mmHg at 60 beats/min [15]. While chronic animal studies are still ongoing, BiVACOR pulsatile operation in vivo studies have been conducted and demonstrate its ability to combine the possible physiologic benefits of a pulse (which was traditionally only afforded by volume-displacement pumps) with the benefits of a rotary pump [16].

The CARMAT TAH (Vélizy-Villacoublay, France) readdresses the challenges of developing a self-contained, totally implantable, durable volume-displacement TAH. However, all the surfaces in contact with blood are lined with bovine pericardial tissue, and the valves are bioprosthetic. Moreover, it is shaped to mimic an actual heart. It contains two chambers that propel pulsatile blood using an alternating, self-contained pusher plate separated by flexible polyurethane membranes filled with fluid. Each chamber is lined with a styrene copolymer membrane and contains two mechanical valves that provide unidirectional flow. A direct driveline actuates the pusher plate into one chamber, which propels the blood forward, while creating negative pressure to fill the opposite chamber. To date, there have been reports of two patients implanted with the CARMAT. One patient was supported for 74 days before electronic device failure and the other was supported for 270 days before mechanical device failure [17].

While strides are being made on TAHs, there are limitations to the use of most TAHs for patients with a body surface area (BSA) less than 1.7 m² and/or an anteroposterior dimension (from sternum to T-10 vertebra) less than 10 cm (e.g. young patients with congenital heart disease or biventricular heart failure). As an example, previous attempts at using the 70 cm³ SynCardia resulted in a higher incidence of complications due to stroke volume–BSA mismatch and pulmonary vein compression (namely intracranial hemorrhage and pulmonary infections). Therefore, SynCardia is developing a positive displacement TAH with a 50-cm³ blood-pumping chamber to enable use in patients with a BSA as low as 1.2 m² (The SynCardia 50/50) [18]. The first report of the SynCardia 50/50 implanted in a human was recently published. The patient survived 55 days after implantation and died as a result of urosepsis. The SynCardia 50/50 performed well throughout the patient’s postoperative course [19]. While clinical trials are still underway, the SynCardia 50/50 should dramatically increase the use of TAHs for use in pediatric patients and small adults.

5. Conclusion

There are still several challenges to overcome in pursuit of a TAH for destination therapy in patients with end-stage heart failure. However, the momentous unmet demand for transplants persists. Whether TAH technology advances to the point where it becomes a viable alternative to transplantation remains to be seen. The SynCardia temporary TAH has been shown to increase heart failure patients’ chances of receiving a replacement by bridging them to transplantation. Thus, mechanical circulatory devices, including TAHs, for end-stage heart failure alleviate some of the disparity in patients waiting for hearts. While there are several challenges to overcome, improved durability, reduced size, better efficiency, and greater autonomous balance between pulmonary and systemic flow intrinsic to rotary pumps might lead to rotary TAHs succeeding where previous attempts have failed to provide a practical, permanent replacement for the failing human heart.

Declaration of interest

WE Cohn is the Chief Medical Officer of BIVACOR. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.